Potassium channel blockers

ABSTRACT

The present invention provides a compound of formula (I) 
                         
or its salts or pharmaceutically acceptable derivatives thereof wherein X 1 , R 1 , R 2 , R 3 , R 4 , and R 5  are defined as set forth in the specification. The compounds are useful as potassium ion channel inhibitors.

FIELD OF THE INVENTION

The present invention relates to compounds of formula (I) which arepotassium channel inhibitors. Compounds in this class may be useful asKv1.3 inhibitors for immunomodulation and the treatment of autoimmune,chronic inflammatory, metabolic diseases and the like. Additionally,compounds in this class may also be useful as Kv1.5 inhibitors for thetreatment or prevention of arrhythmias. Pharmaceutical compositionscomprising the compounds and their use in the treatment of autoimmuneand inflammatory diseases and in the treatment of arrhythmia are alsoprovided.

BACKGROUND

Ion channels are proteins that span the lipid bilayer of the cellmembrane and provide an aqueous pathway through which specific ions suchas Na⁺, K⁺, and Ca⁻ can pass (Herbert, 1998). Potassium channelsrepresent the largest and most diverse sub-group of ion channels andthey play a central role in regulating the membrane potential andcontrolling cellular excitability (Armstrong & Hille, 1998). Potassiumchannels have been categorized into gene families based on their aminoacid sequence and their biophysical properties (for nomenclature seeGutman et al., 2003).

Compounds which modulate potassium channels have multiple therapeuticapplications to several disease areas including autoimmune,inflammatory, cardiovascular, neuronal, auditory, renal, and metabolicmediated diseases (Shieh et al., 2000; Ford et al., 2002, Xie et al,2004, Cahalan et al, 1997). The potassium channel Kv1.3 is found in anumber of tissues including neurons, blood cells, osteoclasts,macrophages, epithelia, and T- and B-lymphocytes. Furthermore, Kv1.3inhibition has been shown to modulate T-cell function which hasimplications in many autoimmune diseases including psoriasis, rheumatoidarthritis, multiple sclerosis, obesity, diabetes and inflammatory boweldisease (Beeton et al., 2006).

Kv1.3 Channel Blockers for Autoimmune Disorders

The role of autoreactive, late-stage, memory T-ceils in the pathogenesisof a variety of autoimmune diseases including psoriasis, rheumatoidarthritis, multiple sclerosis, IBD and others is well established.Activation of T_(EM) cells is followed by substantial up-regulation ofKv1.3 channel expression and, as a result Kv1.3 becomes the predominantroute of potassium efflux from the cell. Thus, selective blockade ofKv1.3 causes membrane depolarisation and inhibition of Ca²⁺ influx,leading to inhibition of cytokine production and cell proliferation andfunction. Kv1.3 thus represents a novel therapeutic target of greatinterest for autoimmune disease control.

T-Cells and Autoimmunity

T-cells are lymphocytes which play a central role in cell mediatedimmunity. One of the major forms of T-cell is the helper T-cell (T_(H)),also known as CD4+ cells which plays an essential role in thedevelopment of autoimmune diseases. Through the production of thecytokine interleukin 2 (IL-2), CD4+ T-cells can create the second maintype of T-cell known as cytotoxic T-cells (CD8+). Naïve (inactive) CD4+and CD8+ T-cells express both proteins (CCR7+CD45RA+) and use thechemokine receptor CCR7 as a key to gain entry into lymph nodes. Withinlymph nodes, the naïve T-cells encounter antigen and through anactivation process, change into “effector” T-cells that producecytokines and proliferate. Once the ensuing immune response subsides,most naïve effectors die, but a few differentiate into long-livedcentral memory cells (T_(CM)). T_(CM) cells, like naïve cells, use CCR7to home to the lymph nodes to encounter their cognate antigen. Uponantigenic stimulation, T_(CM) cells change into “T_(CM) effector” cellsthat produce cytokines and proliferate. They too suffer the same fate asnaïve effectors, the majority dying after the immune response wanes,leaving a few long-lived survivors for further challenge. Repeatedantigenic challenge, as might happen in autoimmune diseases or inchronic infections, causes T_(CM) cells to differentiate intoshort-lived “effector memory T-cells” (T_(CM)) that lack expression ofboth CCR7 and CD45RA, and do not need to home to lymph nodes forantigen-induced activation. A subset of CD8+ T_(EM) cells reacquireCD45RA and become CCR7-CD45RA+ T_(EMRA) cells. Upon activation, bothCD4+ and CD8+ T_(EM) cells change into T_(EM) effectors that migraterapidly to sites of inflammation and produce large amounts of theproinflammatory cytokines, interferon-γ (IFN-γ) and tumor necrosisfactor α (TNFα). In addition, CD8+ T_(EM) effectors carry large amountsof perforin and are therefore immensely destructive (Wulff et al, 2003,Beeton et al, 2005).

Functional Role of KV1.3 in T-cells and Autoimmune Disorders

Human T-cells express two K⁺ channels, Kv1.3 and IKCa1, that provide thecounterbalance cation efflux necessary for the sustained elevation ofcytosolic Ca²⁺ levels required for gene transcription, proliferation andcytokine secretion (Panyi et al, 2004, Chandy et al, 2004). The Kv1.3and IKCa1 (also known, as KCa3.1) channels regulate membrane potentialand facilitate Ca²⁺ signalling in T-lymphocytes. Kv1.3 opens in responseto membrane depolarization and maintains the resting membrane potential(initiation phase), whereas IKCa1 opens in response to an increase incytosolic Ca²⁺ and hyperpolarises the membrane potential (Beeton et al,2001). Selective blockade of K⁺ channels leads to membranedepolarisarion, which in turn inhibits Ca²⁺ influx and shuts downcytokine production and cell proliferation. Early in vitro studies,using channel blocker toxins, clearly demonstrate that Kv1.3 channelsare essential for the synthesis (gene activation) and secretion of thecytokine IL-2 after T-cell activation (Price et al, 1989) and provide arationale for the potential therapeutic use of inhibitors of thischannel in immunological disorders. The role of autoreactive T-cells inthe pathogenesis of autoimmune diseases has clearly been demonstrated inanimal models. Disease-specific, autoreactive T-cells in several otherautoimmune diseases are also reported to exhibit a memory phenotype.Autoreactive T_(EM) cells are also implicated in psoriasis, rheumatoidarthritis, multiple sclerosis, IBD, vitiligo, uveitis, pemphigus,inflammatory myopathies, Hashimito disease, and scleroderma (Beeton etal, 2005). “Late” memory T- and B-cells have been implicated in thedisease progression and tissue damage in a number of autoimmunediseases, in transplant rejection and chronic graft-versus-host disease.Modulators of the Kv1.3 channel may allow selective targeting ofdisease-inducing effector memory T-cells and memory B-cells withoutcompromising the normal immune response and as a result are likely tohave a preferred side-affect profile than agents that bring about moregeneral immunosuppression.

The observation that the Kv1.3 blocker margatoxin (MgTX) effectivelysuppressed the delayed-type hypersensitivity (DTH) response in vivo wasprovided by Koo et al, 1999. In addition MgTX was also shown to inhibitprimary antibody response in non-sensitised animals (secondary antibodyresponse was not affected by MgTX. These latter results are in agreementwith the notion that Kv1.3 channels are predominant in resting Tlymphocytes and regulate their function, white IKCa1 channels are moreimportant in pre-activated T lymphocytes. Correolide (Koo et al, 1999)and PAP-1 (Schmitz et al, 2005) are novel immunosuppressants which blockKv1.3 channels and are effective in the DTH model. Because the cellularcomponents involved in DTH response are similar to those found inautoimmune diseases and allograft rejection, the results obtained arevery promising for the development of Kv1.3 channel blockers as newimmunosuppressants.

In the early 1980's a number of compounds were reported to block Kv1.3channels at micromolar to millimolar concentrations as described byTriggle et al, in “Voltage Gated Ion Channels as Drug Targets” theseinclude classical Kv channel inhibitors such as 4-aminopyridine andtetramethylammonium, and other non specific compounds such as thecalcium activated potassium channel blockers quinine and ceteidil, thephenothiazine antipscychotics chloropromazine and trifluoroperazine, theclassical calcium channel inhibitors verapamil, diltiazem, nifedipineand nitrendipine, and the beta blocker propranolol.

Also in the 1980's natural products extracted from scorpions, snakes andother marine organisms were found to be potent inhibitors of Kv1.3channels, these were primarily short peptides (<70 residues) that arestabilised by multiple sulphide bonds. The first of these potentinhibitors was isolated from the venom of the scorpion. Leiurusquinquestriatus hebraeus and was named charybdotoxin (ChTX) (Sands etal, 1989), there after screening of other scorpion venoms led to theidentification of more potent Kv1.3 blocking toxins, these includemargatoxin (MgTX) (Garcia et al, 1993), agitoxin-2 (Garcia et al, 1994),hongotoxin (Koshchak et al, 1998), pandinus imperator toxin 2 (Pi2)(Peter et al, 2001) and orthochirus scrobiculosus (OSK1) (Mouhat el al,2005) among others. With the exception of OSK1 (300 fold selective overthe nearest related channel) none of the scorpion toxins were selectivefor Kv1.3

One of the most potent and selective Kv1.3 blockers to date, which wasextracted from sea anemone is stichodactyla helianthus toxin (Shk)(Pennington et al, 1996) this has been reported for the treatment ofautoimmune disease through the blockade of Kv1.3 (U.S. Pat. No.6,077,680). Shk and its synthetic derivative Shk-Dap²² with improvedselectivity profile display pico molar activity (Pennington et al, 1998)however, these peptides proved to have unfavourable properties forfurther development.

Recently more novel and selective small molecule Kv1.3 channel blockershave been reported for the management of autoimmune disorders. Theseinclude the iminodihydroquinolines WIN173173 and CP339818 (Nguyen et al,1996), the benzhydryl piperidine UK-78,282 (Hanson et al, 1999),correolide (Felix et al., 1999), cyclohexyl-substituted benzamide PAC(U.S. Pat. No. 6,194,458, WO0025774), sulfamidebenzamidoindane (U.S.Pat. No. 6,083,986), Khellinone (Baell et al., 2004),dichloropenylpyrazolopyrimidine (WO-00140231) and psoralens (Wulff etal., 1998., Vennekamp et al., 2004, Schmitz et al., 2005).

Furthermore, the related Kv1.5 channel is expressed in atrial myocytesand is believed to offer therapeutic opportunities for the management ofatrial fibrillation for several different reasons (see review of Brendeland Peukett, 2002): (i) There is evidence that Kv1.5 underlies thecardiac ultrarapid delayed rectifier (Kv_((ur))) physiological currentin humans due to similar biophysical and pharmacological properties(Wang et al., 1993; and Fedida et al., 1993). This has been supportedwith antisense oligonucleotides to Kv1.5 which have been shown to reduceKv_((ur)) amplitude in human atrial myocytes (Feng et al., 1997). (ii)electrophysiological recordings have demonstrated that Kv_((ur)) isselectively expressed in atrial myocytes, and therefore avoids inducingpotentially fatal ventricular arrhythmia through interfering withventricular repolarization (Amos et al., 1996; Li et al., 1996; andNattel, 2002). (iii) Inhibiting Kv_((ur)) in atrial fibrillation-typehuman atrial myocytes prolonged the action potential duration comparedto normal healthy human atrial myocytes (Courtemanche et al., 1999).(iv) Prolonging the action potential duration by selectively inhibitingKv1.5 could present safer pharmacological interventions for protectingagainst atrial re-entrant arrhythmias such as atrial fibrillation andatrial flutter compared to traditional class III antiarrythmics, byprolonging the atrial refractory period while leaving ventricularrefractoriness unaltered (Nattel et al., 1999, Knobloch et al., 2002;and Wirth et al., 2003). Class III antiarrythmies have been widelyreported as a preferred method for treating cardiac arrhythmias(Colatsky et al., 1990).

Drugs that maintain the sinus rhythm long-term without proarrhythmic orother side effects are highly desirable and not currently available.Traditional and novel class III antiarrythmic potassium channel blockershave been reported to have a mechanism of action by directly modulatingKv1.5 or Kv_((ur)). The known class III antiarrythmics ambasilide (Fenget al., 1997), quinidine (Wang et al., 1995), clofilium (Malayev et al.,1995) and bertosamil (Godreau et al., 2002) have all been reported aspotassium channel blockers of Kv_((ur)) in human atrial myocytes. Thenovel benzopyran derivative, NIP-142, blocks Kv1.5 channels, prolongsthe atrial refractory period and terminates atrial fibrillation andflutter in in vivo canine models (Matsuda et al., 2001), and S9947inhibited Kv1.5 stably expressed in both Xenopus oocytes and Chinesehamster ovary (CHO) cells and Kv_((ur)) in native rat and human cardiacmyocytes (Bachmann et al., 2001). Elsewhere, other novel potassiumchannel modulators which target Kv1.5 or Kv_((ur)) have been describedfor the treatment of cardiac arrhythmias, these include biphenyls(Peukert et al 2003), thiophene carboxylic acid amides (WO0248131),bisaryl derivatives (WO0244137, WO0246162), carbonamide derivatives(WO0100573, WO0125189) anthranillic acid amides (WO2002100825,WO02088073, WO02087568), dihydropyrimidines (WO014023), cycloalkylaminederivatives (WO2005018635), isoqnionolines (WO2005030791), quinolines(WO2005030792), imidazopyrazines (WO205034837), benxopyranols(WO2005037780), isoquinolinones (WO2005046578), cycloakyl derivatives(WO03063797), indane derivatives (WO0146155 WO9804521), tetralinbenzocycloheptane derivatives (WO9937607), thiazolidone andmetathiazanone derivatives (WO9962891), benzamide derivatives(WO0025774), isoquinoline derivatives (WO0224655), pyridazinonederivatives (WO9818475 WO9818476), chroman derivatives (WO9804542),benzopyran derivatives (WO0121610, WO03000675, WO0121609, WO0125224,WO02064581), benzoxazine derivatives (WO0012492), and the novel compoundA1998 purified from Ocean material (Xu & Xu, 2000).

Sulfonamides have been reported to be useful as inhibitors of11-beta-hydroxysteroid dehydrogenase type1, CCR5, H3 receptor andmitotic kinesins amongst others.

Substituted aryl tertiary sulfonamides, wherein position 4 issubstituted with an amide have been claimed as inhibitors of11-betehydroxysteroid dehydrogenase type1, for the treatment andprevention of hyperglycemia in diseases such as type-2 diabetes(WO200406535).

Substituted aryl tertiary sulfonamides, wherein position 3 is optionallysubstituted with substituted alky, alkoxyamino, sulfonyl, acyl, alkoxycarbonyl or aminocarbonyl have been claimed as inhibitors of mitotickinesins as effective anti cancer agents (WO2007056078).

Substituted 1-3 phenyl sulfonamides bearing a benzyl group and an amidogroup have been claimed as useful for the treatment and/or prophylaxisof viral diseases, in particular for the treatment of Hepatitis C (WO2007/110171)

Elsewhere, arylsulophonylaminobenzene derivatives bearing an alkylaminogroup meta to the sulfonamide were found to be inhibitors of Factor Xaand useful in the treatment of arterial and venous thrombotic occlusivedisorders, inflammation, cancer and neurodegenerative diseases (WO96/40100).

Substituted 1,3 phenylsulfonamides containing an amido group meta to thesulfonamide have been claimed as inhibitors of BACE as an effectivemeans for treating and preventing Alzheimer's and related diseasescaused by the production of beta-amyloid (WO 2005/030709).

Substituted 1,3 phenylsulfonamides containing an ether group meta to thesulfonamide have also been claimed as liver X receptor (LXR) modulatorsuseful for the treatment or prevention of diseases associated with theactivity of LXR's (WO2003082205)

It has now surprisingly been found that compounds of general formula (I)set out below act as inhibitors of potassium channels. These compoundsare particularly useful for inhibiting the potassium channel Kv1.3 andtreating diseases associated with the inhibition of the potassiumchannel Kv1.3. This invention is not limited to treating diseasesmediated by Kv1.3, the compounds also being useful to treat diseaseswhich require Kv1.5 potassium channel inhibition for example atrialfibrillation (Marban, 2002, Brendel and Peukert, 2002).

Thus, in a first aspect, the present invention provides a compound offormula (I)

or its salts or pharmaceutically acceptable derivatives thereof wherein;

X₁ is selected from a group consisting of CH₂, C(═O), C(═NH), NC(═O),

R₁ is selected from the group consisting of optionally substitutedarylalkyl, and optionally substituted heteroarylalkyl

R₂ is selected from the group consisting of optionally substitutedalkyl, optionally substituted aryl or heteroaryl or NR₂₄R₂₅

R₃ is selected from the group consisting of hydrogen, halogen, hydroxyl,alkoxy, aryloxy, optionally substituted alkyl, optionally substitutedamino, optionally substituted amino sulfonyl or nitrile;

R₄ is selected from the group consisting of optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted acyl, optionally substitutedsulfonyl, optionally substituted sulfamoyl, optionally substituted aryl,optionally substituted arylalkyl, and optionally substituted heteroarylR₅ may be hydrogen, an optionally substituted alkyl, preferably CH₃ or,NR₄R₅ may form an optionally substituted saturated or partiallysaturated 4-7 membered ring with the general formula (II).

Wherein;

X₂ is C(═O), CH₂, CH(R₆) or C(R₆)(R₆),

X₃ is CH₂, CH(R₇), C(R₇)(R₇), NH, N(R₈), O or S

Each R₆ independently represents optionally substituted amino,optionally substituted amino carbonyl, hydroxyl, optionally substitutedacyl, optionally substituted alkoxy, optionally substituted aryloxy,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted arylalky, optionally substituted aryl oroptionally substituted heteroaryl;

Each R₇ independently represents optionally substituted amino,optionally substituted amino carbonyl, hydroxyl, optionally substitutedacyl, optionally substituted alkoxy, optionally substituted aryloxy,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted arylalky, optionally substituted aryl oroptionally substituted heteroaryl

R₈ is optionally substituted acyl, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted arylalkyl,optionally substituted aryl or optionally substituted heteroaryl;

R₂₄ and R₂₅ are the same or different and each represents hydrogen,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted arylalkyl, optionally substituted aryl oroptionally substituted heteroaryl,

n=1 or 2

m=1, 2 or 3

With the proviso that when X is C═O and R₅ is H then R₄ is not:

Where R₄a, R₅a and R₆a are each independently H, C₁₋₆ alkyl, aryl,heteroaryl, cycloalkyl, or aryl-C₁₋₆ alkyl;

R₁₀a is H or C₁₋₆ alkyl; and

R₁₁ is C₁₋₆alkyl or aryl-C₁₋₆ alkyl

and when X₁ is C═O or CH₂ and R₅ is H then R₄ is not:

Where q is 0 to 5,

R₃b is H, OH or alkoxy and

R₄b is NH₂, phenyl or a C₃₋₁₀ heterocycle.

In one embodiment the invention provides compounds of the followingformula:

or its salts or pharmaceutically acceptable derivatives thereof wherein;

X₁ is selected from a group consisting of CH₂, C(═O), C(═NH), NC(═O),

R₁ is selected from the group consisting of optionally substitutedarylalkyl, and optionally substituted heteroarylalkyl

R₂ is selected from the group consisting of optionally substitutedalkyl, optionally substituted aryl or heteroaryl or NR₂₄R₂₅

R₃ is selected from the group consisting of hydrogen, halogen, hydroxyl,alkoxy, aryloxy, optionally substituted alkyl, optionally substitutedamino, optionally substituted amino sulfonyl or nitrile;

R₄ is selected from the group consisting of optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted acyl, optionally substitutedsulfonyl, optionally substituted sulfamoyl, optionally substituted aryl,optionally substituted arylalkyl, and optionally substituted heteroaryl

R₅ is may be hydrogen, an optionally substituted alkyl, preferably CH₃or, NR₄R₅ may form an optionally substituted saturated or partiallysaturated 4-7 membered ring with the general formula (II).

Wherein;

X₂ is C(═O), or C(R₆)₂,

X₃ is C(R₇)₂, NH, N(R₈), O or S

R₆ for each occurrence independently represents hydrogen, optionallysubstituted amino, optionally substituted amino carbonyl, hydroxyl,optionally substituted acyl, optionally substituted alkoxy, optionallysubstituted aryloxy, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted arylalky, optionallysubstituted aryl or optionally substituted heteroaryl;

R₇ for each occurrence independently represents hydrogen, optionallysubstituted amino, optionally substituted amino carbonyl hydroxyl,optionally substituted acyl, optionally substituted alkoxy, optionallysubstituted aryloxy, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted arylalky, optionallysubstituted aryl or optionally substituted heteroaryl;

R₈ is optionally substituted acyl, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted arylalkyl,optionally substituted aryl or optionally substituted heteroaryl;

R₂₄ and R₂₅ are the same or different and each represents hydrogen,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted arylalkyl, optionally substituted aryl oroptionally substituted heteroaryl,

n=1 or 2

m=1, 2 or 3

With the proviso that when X₁ is C═O and R₅ is H then R₄ is not:

Where R₄a, R₅a and R₆a are each independently H, C₁₋₆ alkyl, aryl,heteroaryl, cycloalkyl, or aryl-C₁₋₆ alkyl;

R₁₀a is M or C₁₋₆ alkyl; and

R₁₁a is C₁₋₆alkyl or aryl-C₁₋₆ alkyl

and when X₁ is C═O or CH₂ and R₅ is H then R₄ is not:

Where q is 0 to 5,

R₃b is H, OH or alkoxy and

R₄ is NH₂, phenyl or a C₃₋₁₀ heterocycle.

As used herein, the following definitions shall apply unless otherwiseindicated.

The term “optionally substituted” means that a group may be substitutedby one or mom substituents which may be the same or different. Whenotherwise not specified, these substituents are selected from alkyl,cycloalkyl, —O—C(halogen)₃ preferably —OCF₃, biaryl, carbocyclic aryl,heteroalicyclic, heteroaryl, acyl, amidino, amido, amino, alkyoxyamino,carbamoyl, carboxy, cyano, ether, hydroxyl, imino, halo, nitro,sulphamoyl, sufonyl, sulphinyl, sulphenyl, sulfonamido or urea.

The term, “alkyl group” as used herein, is typically a linear orbranched alkyl group or moiety containing from 1 to 6 carbon atoms,preferably 2, 3, 4, or 5 carbon atoms Such as a C₁₋₄ alkyl group ormoiety, for example methyl, ethyl, n-propyl, i-propyl, butyl, i-butyland t-butyl. An alkyl group or moiety may be unsubstituted orsubstituted at any position. Typically, it is unsubstituted or carriesone two or three substituents. Suitable substituents include cyano,halogen, hydroxyl, alkylamino, dialkylamino, amido, alkylamido,dialkylamido, alkanoyl, alkoxy, sulfonamide, nitro, aryl and heteroaryl.The alkyl moiety may also be an “unsaturated alkyl” moiety, which meansthat it contains at least one alkene or alkyne moiety. An “alkene”moiety refers to a group consisting of at least two carbon atoms and atleast one carbon-carbon, double bond. An “alkyne” moiety refers to agroup consisting of at least two carbon atoms and at least onecarbon-carbon, triple bond.

The term “cycloalkyl” as used herein refers to mono- or bicyclic ring orring systems consisting of 3 to 11 carbon atoms i.e. 3, 4, 5, 6, 7, 8,10 or 11 carbon atoms. The ring system may be a “saturated ring”, whichmeans that the ring does not contain any alkene or alkyne moieties. Thecycloalkyl group may also be an “unsaturated ring” which means that itcontains at least one alkene or alkyne moiety and the ring system is notaromatic. The cycloalkyl group may be unsubstituted or substituted asdefined herein. In addition to the above mentioned substituents one ormore ring carbon atoms may also be bonded via a double bond to a groupselected from NH, S and O. The cycloalkyl substituent may be bonded viaa linker group such as a C₁₋₆ alkyl group, except where the optionalsubstituent is alkyl. One or more hydrogens of the alkyl group in thelinker may be replaced by a moiety selected from the group consisting ofhydroxy, halo, cyano, amino, thiol, C₁₋₆ alkoxy, C₁₋₆alkylthio, C₁₋₆alkylamino and C₁₋₆ dialkylamino.

The term “aryl group” as used herein, is typically a C₆₋₁₀ aryl groupsuch as phenyl or naphthyl. A preferred aryl group is phenyl. An arylgroup may be substituted or substituted at any position. Typically, itcarries 1, 2, 3 or 4 substituents. Suitable substituents include cyano,halogen, hydroxyl, nitro, trifluoromethyl alkyl, alkylthio, alkoxy,amino, alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,NN-dialkylamino, sulfonamido, aryl and heteroaryl.

The term “carbocyclic” refers to a compound which contains one or morecovalently closed ring structures and the atoms forming the backbone ofthe ring(s) are all carbon atoms. The term thus distinguishescarbocyclic from heterocyclic rings. Carbocyclic groups include both, a“cycloalkyl group”, which means a non-aromatic carbocyclic, and a“carbocyclic aryl” group, which, means an aromatic carbocycle. Thecarbocyclic group may optionally be substituted as defined herein.

The term “heterocyclic” or “heterocyclo” as used herein refers to mono-or bicyclic rings or ring systems which include one or more heteroatomsselected from N, S and O. The rings or ring systems include 1 to 6carbon atoms in addition to the heteroatom(s). The term heterocyclicgroup include both, a “heteroalicyclic” group, which means anon-aromatic heterocyclic and a “heteroaryl” group, which means anaromatic heterocyclic. The heterocyclic moiety may be unsubstituted orsubstituted as defined herein and the substituents, when positionedadjacent to one another, may combine to form cycloalkyl orheteroalicyclic ring systems for example methylendioxy ordifluoromethylendioxy. The heterocyclic substituent may be bonded via acarbon atom or a heteroatom. The heterocyclic group may also include theoxides of nitrogen and sulfur if nitrogen or sulfur are present in thering.

The term “heteroaryl” as used herein refers to mono- or bicyclic ring orring systems which include one or more heteroatoms selected from N, Sand O. The rings or ring systems include 1 to 13 carbon atoms inaddition to the heteroatom(s) and contain at least one aromatic ringwith a heteroatom. The heteroaryl group may also include the oxides ofnitrogen and sulfur if nitrogen or sulfur is present. Examples ofmonocyclic heteroaryl groups include, but are not limited to, furyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,pyridyl, pyrimidyl, pyridazinyl, pyrazinyl and triazinyl. Examples ofbicyclic heterocycles include but are not limited to indolyl,benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl,benzisoxazolyl, benzisothiazolyl, indazolyl, isoquinolinyl, quinolinyl,quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzotriazinyl andthe like. Examples of tricyclic heterocycles include but are not limitedto thianthrenyl, xanthenyl, phenoxathiinyl, carbazolyl, carbolinyl,phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl,phenothiazinyl and phenoxazinyl. The heteroaryl group may beunsubstituted or substituted as defined herein. The substituents, whenpositioned adjacent to one another, may combine to form a cycloalkyl orheteroalicyclic ring for example methylendioxy anddifluoromethylendioxy. The heteroaryl substituent may be bonded via acarbon atom or a heteroatom.

The term “arylalkyl”, as used herein, refers to a chemical moiety offormula aryl-C₁₋₆ alkyl or C₁₋₆ alkyl-aryl as those terms are definedherein.

The term “heteroarylalkyl”, used as herein, refers to a chemical moietyof formula Heteroaryl-C₁₋₆ alkyl or C₁₋₆ alkyl-heteroaryl as those termsare defined herein.

The term “acyl”, as used herein, refers to a chemical moiety of formula(CH₂)yC(═O)Rz wherein y is 1-6

The term “amidino” refers to a chemical moiety with the formula(CH₂)yC(═NH)NRzR′z wherein y is 1-6.

The term “amido” refers to both, a “C-amido” group which means achemical moiety with the formula —C(═O)NRzR′z and a “N-amido” groupwhich means a chemical moiety with the formula —NRzC(═O)R′z.

The term “amine” or “amino” refers to a chemical moiety of formula—NRzR′z. The definition of an amine is also understood to include theirN-oxides.

A “cyano” group refers to a chemical moiety of formula —CN.

The term “hydroxy” or “hydroxyl” as used herein, refers to a chemicalmoiety of formula —OH.

The term “halogen” or “halo” refers to an atom selected from the groupconsisting of fluorine, chlorine, bromine and iodine.

The term “alkanoyl”, as used herein, refers to a chemical moiety withthe formula —C(═O)Rz.

The term “sulfone” or “sulfonyl” refers to a chemical moiety with theformula —S(═O)₂Rz.

The term “sulfinyl” refers to a chemical moiety with the formula—S(═O)Rz.

The term “sulfenyl” refers to a chemical moiety with the formula —SRz.

A “sulfamoyl” group refers to a chemical moiety with the formula—NRz-S(═O)₂NRzR′z.

The term “sulfonamido” refers to both an “S-sulfonamido” group whichmeans a chemical moiety with the formula —S(═O)₂NRzR′z and an“N-sulfonamido” group which means a chemical moiety with the formula—N—S(═O)₂R′z.

The term “thiocarbonyl” refers to a chemical moiety with the formula(CH₂)yC(═S)Rz wherein y is 1-6.

The term “thio” or “thiol”, as used herein, refers to a chemical moietyof formula —SH.

The term “thioamide” refers to both a “C-thioamido” group which means achemical moiety with the formula (CH₂)yC(═S)NRzR′z and a “N-thioamido”group which means a chemical moiety with the formula (CH₂)yNRzC(═S)R′zwherein, y is 1-6.

An “urea” group refers to a chemical moiety of formula —NRzC(═O)NRzR′z.

Rz and R′z are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, cycloalkyl, C₁₋₆ alkoxy, aryl-C₁₋₆ alkyl, aryl andheteroaryl.

In a preferred embodiment;

X₁ is C(═O).

R₂ is selected from NR₂₄R₂₅. Preferably R₂₄ and R₂₅ are the same ordifferent and each represents hydrogen, or optionally substituted C₁₋₆alkyl. More preferably, R₂₄ and R₂₅ are CH₃.

Alternatively, R₂ is selected from compounds of formula (III), (IV) or(V)

Wherein;

A, D, E, G, and J are the same or different and each represents C, or Nwith the proviso that in each instance at least one of A, D, E, G, or Jis N;

When R₂ is selected from compounds of formula (III), E may alsorepresent O or S; and

When R₂ is selected from compounds of formula (IV), A may also representO or S;

Preferred moities of formula (III), (IV) and (V) are Imidazole,Pyrazole, Pyrrole, Oxazole, Oxadiazole, Thiazole, Thiadiazole, Pyridine,Pyrimidine, Pyrazine, Pyridazine, and Triazine. More preferably R₂ isselected from Imidazole, Pyrazole, or Pyridine

R₉ and R₁₀ are the same or different and each represents hydrogen,halogen, hydroxyl, nitrile, optionally substituted amino, optionallysubstituted acyl, optionally substituted C₁₋₃ alkyl, optionallysubstituted arylalky, optionally substituted aryl or optionallysubstituted heteroaryl or may be taken together to form an optionallysubstituted saturated or partially saturated 5-7 membered heterocyclicor carbocyclic ring.

Preferably and R₉ and R₁₀ are alkyl, more preferably CH₃.

Alternatively, R₂ is selected from compounds of formula (VI)

R₁₁, R₁₂, R₁₄, and R₁₅ are the same or different and each representshydrogen, halogen, hydroxyl, optionally substituted amino, optionallysubstituted acyl, nitrile, optionally substituted C₁₋₃ alkyl, any of thepairs R₁₁ and R₁₂, or R₁₂ and R₁₃, or R₁₃ and R₁₄, or R₁₄ and R₁₅ or maybe taken together to form an optionally substituted saturated orpartially saturated 5-7 membered heterocyclic or carbocyclic ring.

Preferred moities of formula (VI) include phenyl, fluorophenyl,chlorophenyl, cyanophenyl, aminophenyl, acetamidophenyl,tetrahydrobenzofuran, benzopyran, dihydrobenzodioxin, benzoxazinone,benzooxadiazole, benzodioxole, indoline, indole, indazole, andbenzomorpholine. More preferred moities are phenyl, fluorophenyl,cyanophenyl, tefrahydrobenzofuran, benzopyran, dihydrobenzodioxin,benzoxazinone, benzooxadiazole, benzodioxole, indoline, andbenzomorpholine.

Perferably R¹ is

Wherein R₁₆, R₁₇, R₁₈, R₁₉ and R₂₀ are the same or different and eachrepresents hydrogen, halogen, hydroxyl, optionally substituted amino,optionally substituted acyl, nitrile, optionally substituted C₁₋₃ alkylor optionally substituted alkoxy; R₂₁ and R₂₂ are the same or differentand each represents hydrogen, hydroxyl, and optionally substituted C₁₋₃alkyl. Preferably R₁₇, R₁₈ and R₁₉ are the same or different and eachrepresents H, Cl, F, or CH₃. More preferably, R₁₇, R₁₈ and R₁₉ are thesame or different and each represents H or Cl

Preferably R₃ is H, F or CH₃. More preferably R₃ is H or F.

R₄ is preferably selected from the group consisting of optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, substituted aryl, optionally substitutedarylalkyl, and optionally substituted heteroaryl. Preferred examplesinclude methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl,cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, 2-hydroxyethyl,hydroxypropyl, hydroxybutyl, propane-1,3-diol, methoxyethyl, phenyl,benzyl, phenethyl, 3-phenylpropyl, piperidinyl, pyrollidinyl,morpholinyl, piperazinyl, indazolyl, pyridyl, thiadiazolyl, andthiazolyl.

R₅ is preferably selected from hydrogen, optionally substituted alkyl,preferably CH₃ or NR₄R₅ may form an optionally substituted saturated orpartially saturated 4-7 membered ring with the general formula (II).More preferably, R₅ is selected from hydrogen, CH₃ or NR₄R₅ may form anoptionally substituted saturated or partially saturated 4-6 memberedring with the general formula (II) examples of which include azetidinyl,pyrrolidinyl, piperazinyl, piperidinyl.

X₂ is C(═O), CH₂ or CH(R₆) or C(R₆)(R₆),

X₃ is CH₂, CH(R₇), C(R₇)(R₇), NH, N(R₈), or O

Wherein;

Each R₆ independently represents halogen, hydroxyl, optionallysubstituted alkoxy, optionally substituted aryloxy, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted arylalky, optionally substituted aryl or optionallysubstituted heteroaryl. More preferably, R₆ independently representsfluoro, hydroxyl and methyl.

Each R₇ independently represents halogen, hydroxyl, optionallysubstituted acyl, optionally substituted alkoxy, optionally substitutedaryloxy, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted arylalky, optionally substituted arylor optionally substituted heteroaryl independently represents fluoro,hydroxyl, cyclohexylmethyl, phenyl, fluorophenyl and phenoxy.

R₈ is optionally substituted acyl, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted arylalkyl,optionally substituted aryl or optionally substituted heteroaryl;

More preferred compounds are those selected from compounds of formula(VIII);

Wherein;

R₂ is selected from NR₂₄R₂₅ or compounds of formula (III), (IV) (V) or(VI), R₃, R₄, R₅, R₁₆, R₁₇, R₁₈, R₁₉ and R₂₀ are as defined above.

Most preferred compounds are those selected from compounds of formula(IX);

Wherein;

R₂ is selected from NR₂₄R₂₅ or compounds of formula (III), (IV), (V) or(VI) as defined.

R₃, R₄, R₅, R₁₇, R₁₈, and R₁₉ are as defined above.

Particularly Preferred Compounds of the Invention Include:

-   3-[(4-Chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-N-(2-hydroxyethyl)-benzamide-   N-Benzyl-3-[benzyl-(1-methyl-1H-imidazole-4-sulfonyl)-amino]-benzamide-   3-[Benzyl-(pyridine-3-sulfonyl)-amino]-N-isopropyl-benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-(1H-indazol-6-yl)-benzamide-   3[(4-Acetylamino-benzenesulfonyl)-benzyl-amino]-N-isopropyl-benzamide-   5-[Benzyl-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-sulfonyl)-amino]-2-fluoro-N-isopropyl-benzamide-   3-[(4-Cloro-benzyl)-(2-methyl-2H-pyrazole-3-sulfonyl)-amino]-N-isopropyl-benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-benzyl-benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-isopropyl-benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-phenethyl-benzamide-   N-Benzyl-N-[3-(4-phenyl-piperidine-1-carbonyl)-phenyl]-benzenesulfonamide-   N-Benzyl-N-[3-(3-phenyl-piperidine-1-carbonyl)-phenyl]-benzenesulfonamide-   N-Benzyl-N-[3-(2-phenyl-morpholine-4-carbonyl)-phenyl]-benzenesulfonamide-   N-Benzyl-N-[3-(4-phenoxy-piperidine-1-carbonyl)-phenyl]-benzenesulfonamide-   3-(Benzenesulfonyl-benzyl-amino)-N-(3-phenyl-propyl)-benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-methyl-benzamide-   3-(benzenesulfonyl-benzyl-amino)-N-tert-butyl-benzamide-   N-Benzyl-N-[3-(3-phenyl-piperidine-1-carbonyl)-phenyl]-methanesulfonamide-   N-Benzyl-N-[3-(2-phenyl-morpholine-4-carbonyl)-phenyl]-methanesulfonamide-   N-Benzyl-N-[3-(4-phenoxy-piperidine-1-carbonyl)-phenyl]-methanesulfonamide-   N-Benzyl-N-[3-(3-(4-phenyl-piperidine-1-carbonyl)-phenyl]-methanesulfonamide-   1-Methyl-1H-imidazole-4-sulfonic acid    benzyl-[3-(4-phenyl-piperidine-1-carbonyl)-phenyl]-amide-   N-Benzyl-N-[3-(3-(morpholine-4-carbonyl)-phenyl]-benzenesulfonamide-   3-(Benzenesulfonyl-benzyl-amino)-N-pyridin-2-ylmethyl-benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-(1H-indazol-5-yl)-benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-(4-imidazol-1-yl-phenyl)-benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-(4-pyrazol-1-yl-phenyl)-benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-[1,3,4]thiadiazol-2-yl-benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-thiazol-2-yl-benzamide-   N-[4-(Aminocarbonyl)phenyl]-3-[benzyl(phenylsulfonyl)amino]benzamide-   N-[3-(Aminocarbonyl)phenyl]-3-[benzyl(phenylsulfonyl)amino]benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-phenyl-benzamide-   1-Methyl-1H-imidazole-4-sulfonic acid    benzyl-[3-(2-phenyl-morpholine-4-carbonyl)-phenyl]-amide-   3-[Benzyl-(1,2-dimethyl-1H-imidazole-4-sufonyl)-amino]-N-isopropyl-benzamide-   3-[Benzyl-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-N-isopropyl-benzamide-   3-[Benzyl-(2,4-dimethyl-thiazole-5-sulfonyl)-amino]-N-isopropyl-benzamide-   N-Benzyl-2-fluoro-N-[3-(morpholine-4-carbonyl)-phenyl]-benzenesulfonamide-   3-[Benzyl-(2-fluoro-benzenesulfonyl)-amino]-N,N-dimethyl-benzamide-   3-[Benzyl-(3-fluoro-benzenesulfonyl)-amino]-N,N-dimethyl-benzamide-   N-Benzyl-4-fluoro-N-[3-(morpholine-4-carbonyl)-phenyl]-benzenesulfonamide-   3-[Benzyl-(4-fluoro-benzenesulfonyl)-amino]-N,N-dimethyl-benzamide-   3-[Benzyl-(4-fluoro-benzenesulfonyl)-amino]-N-isopropyl-benzamide-   1-Methyl-1H-imidazole-4-sulfonic acid    benzyl-{3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-phenyl}-amide-   3-[Benzyl-(2-fluoro-benzenesulfonyl)-amino]-N-isopropyl-benzamide-   3-[Benzyl-(3-fluoro-benzenesulfonyl)-amino]-N-isopropyl-benzamide-   1-Methyl-1H-imidazole-4-sulfonic acid    benzyl-[3-(4-cyclohexylmethyl-piperazine-1-carbonyl)-phenyl]-amide-   3-[Benzyl-(2,3-dihydro-benzofuran-5-sulfonyl)-amino]-N-isopropyl-benzamide-   3-[Benzyl-(2,2-dimethyl-chroman-6-sulfonyl)-amino]-N-isopropyl-benzamide-   3-[Benzyl-(2,3-dihydro-benzo[1,4]dioxine-6-sulfonyl)-amino]-N-isopropyl-benzamide-   3-[(1-Acetyl-2,3-dihydro-1H-indole-5-sulfonyl)-benzyl-amino]-N-isopropyl-benzamide-   3-[Benzyl-(2-methyl-2H-pyrazole-3-sulfonyl)-amino]-N-isopropyl-benzamide-   3-[Benzyl-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonyl)-amino]-N-isopropyl-benzamide-   3-[Benzyl-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-sulfonyl)-amino]-N-isopropyl-benzamide-   2,3-Dihydro-benzo[1,4]dioxine-6-sulfonic acid    benzyl-[3-(morpholine-4-carbonyl)-phenyl]-amide-   4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonic acid    benzyl-[3-(morpholine-4-carbonyl)-phenyl]-amide-   Benzo[1,2,5]oxadiazole-4-sulfonic acid    benzyl-[3-(morpholine-4-carbonyl)-phenyl]-amide-   Benzo[1,3]dioxole-5-sulfonic acid    benzyl-[3-(morpholine-4-carbonyl)-phenyl]-amide-   3-(Benzenesulfonyl-benzyl-amino)-N-cyclopropyl-benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-cyclobutyl-benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-cyclopentyl-benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-(2-hydroxy-1-methyl-ethyl)-benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-(1-hydroxymethyl-propyl)-benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-(2-hydroxy-propyl)-benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-isobutyl-benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-ethyl-benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-(2-methoxy-ethyl)-benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-(2-hydroxy-ethyl)-benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-propyl-benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-(3-hydroxy-propyl)-benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-(4-hydroxy-butyl)-benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-cyclopropylmethyl-benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-(2-hydroxy-1-hydroxymethyl-ethyl)-benzamide-   3-(Benzenesulfonyl-benzyl-amino)-N-((R)-1-hydroxymethyl-propyl)-benzamide-   5-[(Benzo[1,2,5]oxadiazole-4-sulfonyl)-benzyl-amino]-2-fluoro-N-isopropyl-benzamide-   5-(Benzenesulfonyl-benzyl-amino)-2-fluoro-N-isopropyl-benzamide-   5-[Benzyl-(1-methyl-1H-imidazole-4-sulfonyl)-amino]-2-fluoro-N-isopropyl-benzamide-   5-[Benzyl-(4-fluoro-benzenesulfonyl)-amino]-2-fluoro-N-isopropyl-benzamide-   5-[Benzyl-(2,3-dihydro-benzo[1,4]dioxine-6-sulfonyl)-amino]-2-fluoro-N-isopropyl-benzamide-   5-[Benzyl-(4-cyano-benzenesulfonyl)-amino]-2-fluoro-N-isopropyl-benzamide-   5-[Benzyl-(3-cyano-benzenesulfonyl)-amino]-2-fluoro-N-isopropyl-benzamide-   5-[Benzyl-(2-cyano-benzenesulfonyl)-amino]-2-fluoro-N-isopropyl-benzamide-   5-[(Benzo[1,3]dioxole-5-sulfonyl)-benzyl-amino]-2-fluoro-N-isopropyl-benzamide-   5-[(Benzo-(2,3-dihydro-benzofuran-5-sulfonyl)amino]-2-fluoro-N-isopropyl-benzamide-   5-[(Benzyl-(pyridine-3-sulfonyl)-amino]-2-fluoro-N-isopropyl-benzamide-   5-[(4-Acetylamino-benzenesulfonyl)-benzyl-amino]-2-fluoro-N-isopropyl-benzamide-   3-[(4-Chloro-benzyl)-(pyridine-3-sulfonyl)-amino]-N-isopropyl-benzamide-   3-[(4-Chloro-benzyl)-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-sulfonyl)-amino]-N-isopropyl-benzamide-   3-[(4-Chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-N-isopropyl-benzamide-   3-[(4-Chloro-benzyl)-(1-methyl-1H-imidazole-4-sulfonyl)-amino]-N-isopropyl-benzamide-   5-[(Benzyl-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-2-fluoro-N-isopropyl-benzamide-   3-[(4-Chloro-benzyl)-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-sulfonyl)-amino]-N-isopropyl-benzamide-   3-[(4-Chloro-benzyl)-(1,2-dimethyl-1H-imidazole-4-sulfonyl)-amino]-N-isopropyl-benzamide-   5-[(Benzyl-(1,2-dimethyl-1H-imidazole-4-sulfonyl)-amino]-2-fluoro-N-isopropyl-benzamide-   5-[(Benzyl-(2-methyl-2H-pyrazole-3-sulfonyl)-amino]-2-fluoro-N-isopropyl-benzamide-   5-[(4-chloro-benzyl)-(pyridine-3-sulfonyl)-amino]-2-fluoro-N-isopropyl-benzamide-   5-[(4-chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-2-fluoro-N-isopropyl-benzamide-   5-[(4-chloro-benzyl)-(2-methyl-2H-pyrazole-3-sulfonyl)-amino]-2-fluoro-N-isopropyl-benzamide-   5-[(4-chloro-benzyl)-(1,2-dimethyl-1H-imidazole-4-sulfonyl)-amino]-2-fluoro-N-isopropyl-benzamide-   5-[(4-chloro-benzyl)-(1-methyl-1H-pyrazole-4-sulfonyl)-amino]-2-fluoro-N-isopropyl-benzamide-   5-[(4-Chloro-benzyl)-(3-cyano-benzenesulfonyl)-amino]-2-fluoro-N-(2-hydroxy-ethyl-benzamide-   5-[(4-Chloro-benzyl)-(3-cyano-benzenesulfonyl)-amino]-2-fluoro-N-(1-hydroxymethyl-propyl-benzamide-   N-(4-Chloro-benzyl)-3-cyano-N-[4-fluoro-3-(3-hydroxy-azetidine-1-carbonyl)-phenyl]-benzenesulfonamide-   5-[(4-Chloro-benzyl)-(3-cyano-benzenesulfonyl)-amino]-2-fluoro-N-(2-hydroxy-1-hydroxymethyl-ethyl)-benzamide-   5-[(4-Chloro-benzyl)-(3-cyano-benzenesulfonyl)-amino]-2-fluoro-N-(2-hydroxy-1-methyl-ethyl)-benzamide-   5-[(4-Chloro-benzyl)-(3-cyano-benzenesulfonyl)-amino]-2-fluoro-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzamide-   5-[(4-Chloro-benzyl)-(3-cyano-benzenesulfonyl)-amino]-2-fluoro-N-(2-methoxy-ethyl)-benzamide-   N-(4-Chloro-benzyl)-3-cyano-N-[4-fluoro-3-(3-hydroxy-piperidine-1-carbonyl)-phenyl]-benzenesulfonamide-   N-(4-Chloro-benzyl)-3-cyano-N-[4-fluoro-3-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-phenyl]-benzenesulfonamide-   3-[(4-Chloro-benzyl)-(pyridine-3-sulfonyl)-amino]-N-(2-hydroxy-ethyl)-benzamide-   3-[(4-Chloro-benzyl)-(pyridine-3-sulfonyl)-amino]-N-(2-hydroxy-1-methyl-ethyl)-benzamide-   3-[(4-Chloro-benzyl)-(pyridine-3-sulfonyl)-amino]-N-(1-hydroxymethyl-propyl)-benzamide-   Pyridine-3-sulfonic acid    (4-chloro-benzyl)-[3-(3-hydroxy-azetidine-1-carbonyl)-phenyl]-amide-   Pyridine-3-sulfonic acid    (4-chloro-benzyl)-[3-(3-hydroxy-piperidine-1-carbonyl)-phenyl]-amide-   3-[(4-Chloro-benzyl)-(pyridine-3-sulfonyl)-amino]-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzamide-   3-[(4-Chloro-benzyl)-(pyridine-3-sulfonyl)-amino]-N-(2-methoxy-ethyl)-benzamide-   3-[(4-Chloro-benzyl)-(pyridine-3-sulfonyl)-amino]-N-cyclopropyl-benzamide-   3-[(4-Chloro-benzyl)-(pyridine-3-sulfonyl)-amino]-N-cyclopentyl-benzamide-   Pyridine-3-sulfonic acid    (4-chloro-benzyl)-[3-((R)-3-fluoro-pyrrolidine-1-carbonyl)-phenyl]-amide-   3-[(4-Chloro-benzyl)-(pyridine-3-sulfonyl)-amino]-N-cyclobutyl-benzamide-   Pyridine-3-sulfonic acid    [3-(azetidine-1-carbonyl)-phenyl]-(4-chloro-benzyl)-amide-   3-[(4-Chloro-benzyl)-(1-methyl-1H-imidazole-4-sulfonyl)-amino]-N-methyl-benzamide-   3-[(4-Chloro-benzyl)-(1-methyl-1H-imidazole-4-sulfonyl)-amino]-N-ethyl-benzamide-   3-[(4-Chloro-benzyl)-(1-methyl-1H-imidazole-4-sulfonyl)-amino]-N-(2-methoxy-ethyl)-benzamide-   3-[(4-Chloro-benzyl)-(1-methyl-1H-imidazole-4-sulfonyl)-amino]-N-cyclopropyl-benzamide-   3-[(4-Chloro-benzyl)-(1-methyl-1H-imidazole-4-sulfonyl)-amino]-N-cyclopentyl-benzamide-   3-[(4-Chloro-benzyl)-(1-methyl-1H-imidazole-4-sulfonyl)-amino]-N-cyclobutyl-benzamide-   1-Methyl-1H-imidazole-4-sulfonic acid    [3-(azetidine-1-carbonyl)-phenyl]-(4-chloro-benzyl)-amide-   3-[(4-Chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-N-methyl-benzamide-   3-[(4-Chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-N-ethyl-benzamide-   3-[(4-Chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-N-(2-methoxy-ethyl)-benzamide-   3-[(4-Chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-N-cyclopropyl-benzamide-   3-[(4-Chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-N-cyclobutyl-benzamide-   1-Methyl-1H-pyrazole-4-sulfonic acid    [3-(azetidine-1-carbonyl)-phenyl]-(4-chloro-benzyl)-amide-   1-Methyl-1H-pyrazole-3-sulfonic acid    (4-chloro-bnezyl-[3-(3-methyl-piperidine-1-carbonyl)-phenyl]-amide-   3-[(4-Chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-N-cyclopentyl-benzamide-   3-[(4-Chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-N-(2-hydroxy-1-methyl-ethyl)-benzamide-   3-[(4-Chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-N-(1-hydroxymethyl-propyl)-benzamide-   3-[(4-Chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzamide-   3-[(4-chloro-benzyl)-(2-methyl-2H-pyrazole-3-sulfonyl)-amino]-N-cyclobutyl-benzamide-   3-[(4-chloro-benzyl)-(2-methyl-2H-pyrazole-3-sulfonyl)-amino]-N-cyclopentyl-benzamide

As used herein, a pharmaceutically acceptable salt is a salt with apharmaceutically acceptable acid or base. Pharmaceutically acceptableacids include both inorganic acids such as hydrochloric, sulphuric,phosphoric, diphosphoric, hydrobromic or nitric acid and organic acidssuch as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric,benzoic, acetic, methanesulfonic, ethanesulfonic, benzenesulfonic orp-toluenesulfonic. Pharmaceutically acceptable bases include alkalimetal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium ormagnesium) hydroxides and organic bases such as alkyl amines, arylalkylamines or heterocyclic amines.

The compounds of the invention may contain one or more chiral centres.For the avoidance of doubt, the chemical structures depicted herein areintended to embrace all stereo isomers of the compounds shown, includingracemic and non racemic mixtures and pure enantiomers and/ordiastereoisomers.

As discussed herein, the compounds of the invention are useful in thetreatment of various conditions. Thus, in a second aspect, the presentinvention provides a compound of formula (I) as defined herein, for usein medicine. Preferably the compound is used to prevent or treatconditions which require inhibition of potassium channels, such asimmunological disorders, including psoriasis, rheumatoid arthritis andmultiple sclerosis.

In a further aspect the present invention provides a pharmaceuticalformulation comprising at least one compound of formula (I) or asdefined herein and optionally one or more excipients, carriers ordiluents.

The compositions of the invention may be presented in unit dose formscontaining a predetermined amount of each active ingredient per dose.Such a unit may be adapted to provide 5-100 mg/day of the compound,preferably either 5-15 mg/day, 10-30 mg/day, 25-50 mg/day 40-80 mg/dayor 60-100 mg/day. For compounds of formula I, doses in the range100-1000 mg/day are provided, preferably either 100-400 mg/day, 300-600mg/day or 500-1000 mg/day. Such doses can be provided in a single doseor as a number of discrete doses. The ultimate dose will depend on thecondition being treated, the route of administration and the age, weightand condition of the patient and will be at the doctor's discretion.

The compositions of the invention may be adapted for administration byany appropriate route, for example by the oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) route. Such formulations maybe prepared by any method known in the art of pharmacy, for example bybringing into association the active ingredient with the carrier(s) orexcipient(s).

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318 (1986).

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For applications to the eye or other external tissues, for example themouth and skin, the formulations are preferably applied as a topicalointment or cream. When formulated in an ointment, the active ingredientmay be employed with either a paraffinic or a water-miscible ointmentbase. Alternatively, the active ingredient may be formulated in a creamwith an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical administration to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in themouth include lozenges, pastilles and mouth washes.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration wherein thecarrier is a solid include a coarse powder having a particle size forexample in the range 20 to 500 microns which is administered in themanner in which snuff is taken, i.e. by rapid inhalation through thenasal passage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or as nasal drops, include aqueous oroil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists which may be generated by means ofvarious types of metered dose pressurised aerosols, nebulizers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets.

Preferred unit dosage formulations are those containing a daily dose orsub-dose, as herein above recited, or an appropriate fraction thereof,of an active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations may also include other agentsconventional in the art having regard to the type of formulation inquestion, for example those suitable for oral administration may includeflavouring agents.

The compositions of the invention can be used to treat conditions whichrequire inhibition of potassium channels, for example in the treatmentof immunological disorders and arrythmia. Thus, in further aspects, thepresent invention provides:

(i) A method of treating or preventing a disorder which requirespotassium channel inhibition, eg immunological disorders comprisingadministering to a subject an effective amount of at least one compoundof the invention or a pharmaceutical composition of the invention

and

(ii) the use of a compound of the invention in the manufacture of amedicament for use in potassium channel inhibition.

In particular, the medicament is for use in the treatment or preventionof psoriasis, rheumatoid arthritis, multiple sclerosis otherimmunological disorders and arrythmia.

Preferred embodiments of the first aspect apply to all other aspectsmutatis mutandis.

The compounds of formula (I) may be prepared by conventional routes, forexample those set out in Schemes 1 to 6 shown below.

Compounds of formula (I) where X₁ is C═O may be prepared from compoundsof formula (X) where A is OH and amines of formula NHR₄R₅ together witha coupling reagent such as1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) or2-(7-aza-1H-benztriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU) utilising standard methods such as reactionin solvent such as tetrahydrofuran, acetonitrile or dimethylformamide atrange of temperatures from ambient to reflux temperature optionally inthe presence of a activating agent such as hydroxybenzotriazole (HOBT).Alternatively, compounds of formula (I) may be prepared from compoundsof formula (X) where A is Cl and amines of formula NHR₄R₅ in thepresence of a base for example triethylamine utilising standard methodssuch as reaction in solvent such as tetrahydrofuran, acetonitrile ordichloromethane at range of temperatures from ambient to refluxtemperature. Compounds of formula NHR₄R₅ are available from commercialsuppliers or may be prepared by standard published methods familiar tothose skilled in the art.

Compounds of formula (X) where A is OH may be prepared from compounds Offormula (XI) by removal of a suitable protecting group P. In a preferredinstance P is a tertiary butyl group. Removal of this protecting groupmay be accomplished using standard methods of acidic or basic hydrolysisor via protolytic decomposition for example treatment withtrifluoroacetic acid in solvent such as tetrahydrofuran, acetonitrile,dichloromethane or toluene at a range of temperatures from ambient toreflux temperature.

Compounds of formula (XI) may be prepared, from compounds of formula(XII) and sulfonyl chlorides or sulfamoyl chlorides of formula R₂SO₂Clwhere R₂ is defined as above in the presence of a base, for exampletriethylamine, diisopropylamine or pyridine, utilizing standard methodssuch as reaction in solvent such as tetrahydrofuran, acetonitrile,dichloromethane or toluene at a range of temperatures from ambient toreflux temperature. Compounds of formula R₂SO₂Cl are either commerciallyavailable or may be prepared by standard published methods known tothose skilled in the art.

Compounds of formula (XII) may be prepared from compounds of formula(XIII) via reductive amination of a ketone or aldehyde of formula R₁═O.The reaction may be performed in a one pot procedure with in situformation and reduction of the imine or via a two stage process wherethe imine is isolated prior to reduction. Imine formation is performedunder acid catalysis, suitable catalysts include acetic acid. Reductionmay be performed using standard methods such as reaction in solvent suchas tetrahydrofuran, acetonitrile, dichloromethane or toluene at a rangeof temperatures from ambient to reflux temperature with a suitablereductant such as sodium triacetoxyborohydride or sodiumcyanoborohydride, the reduction may also be performed using catalytichydrogenation. Compounds of formula (XIII) are either commerciallyavailable or may be prepared by standard published methods known tothose skilled in the art.

Compounds of formula (XI) may also be prepared from compounds of formula(XIV) where P is a suitable protecting group, in a preferred instance atertiary butyl group, via alkylation of the sulfonamide in a preferredinstance with an alkyl bromide of formula R₁—Br in the presence of abase such as cesium carbonate or potassium carbonate, optionally in thepresence of a phase transfer catalyst such as tetrabutylammoniumbromide, utilizing standard methods such as reaction in solvent such astetrahydrofuran, acetonitrile, dichloromethane, dimethylformamide ortoluene at a range of temperatures from ambient to reflux temperature.Compounds of formula R₁—Br are either commercially available or may beprepared by standard published methods known to those skilled in theart.

Compounds of formula (XIV) may be prepared from compounds of formula(XIII) and sulfonyl chlorides of formula R₂SO₂Cl in the presence of abase, for example triethylamine, diisopropylamine or pyridine, utilizingstandard methods such as reaction in solvent such as tetrahydrofuran,acetonitrile, dichloromethane or toluene at a range of temperatures fromambient to reflux temperature. Compounds of formula R₂SO₂Cl are eithercommercially available or may be prepared by standard published methodsknown to those skilled in the art.

Compounds of formula (I) may also be prepared from compounds of formula(XVIII) and sulfonyl chlorides of formula R₂SO₂Cl in the presence of abase, for example triethylamine, diisopropylamine or pyridine, utilizingstandard methods such as reaction in solvent such as tetrahydrofuran,acetonitrile, dichloromethane or toluene at a range of temperatures fromambient to reflux temperature. Compounds of formula R₂SO₂Cl are eithercommercially available or may be prepared by standard published methodsknown to those skilled in the art.

Compounds of formula (XVIII) may be prepared from the reaction ofcompounds of formula (XVII) and amines of formula NHR₄R₅ together with acoupling reagent such as 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide(EDC) or 2(7-aza-1H-benztriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU) utilising standard methods such as reactionin solvent such as tetrahydrofuran, acetonitrile or dimethylformamide atrange of temperatures from ambient to reflux temperature. Compounds offormula NHR₄R₅ are either commercially available or may be prepared bystandard published methods familiar to those skilled in the art.

Compounds of formula (XVII) may be prepared from compounds of formula(XII) by removal of a protecting group in a preferred instance atertiary butyl group. This may be accomplished by standard methods ofacidic or basic hydrolysis or via protolytic decomposition such astrifluoroacetic acid in solvent such as tetrahydrofuran, acetonitrile,dichloromethane or toluene at a range of temperatures from ambient toreflux temperature.

Compounds of formula (XVIII) may also be prepared from compounds offormula (XV) via reductive amination of a ketone or aldehyde of formulaR₁═O. The reaction may be performed in a one pot procedure with in situformation and reduction of the imine or via a two stage process wherethe imine is isolated and purified prior to reduction. Imine formationis performed under acid catalysis, suitable catalysts include aceticacid. Reduction may be performed using standard methods such as reactionin solvent such as tetrahydrofuran, acetonitrile, dichloromethane ortoluene at a range of temperatures from ambient to reflux temperaturewith a suitable reductant such as sodium triacetoxyborohydride or sodiumcyanoborohydride, the reduction may also be performed using catalytichydrogenation.

Compounds of formula (XV) may be prepared from the reaction of compoundsof formula (XVI) and amines of formula NHR₄R₅ together with a couplingreagent such as 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) or2-(7-aza-1H-benztriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU) utilising standard methods such as reactionin solvent such as tetrahydrofuran, acetonitrile or dimethylformamide atrange of temperatures from ambient to reflux temperature. Compounds offormula NHR₄R₅ are either commercially available or may be prepared bystandard published methods familiar to those skilled in the art.Compounds of formula (XVI) am either commercially available or may beprepared by standard published methods familiar to those skilled in theart.

As discussed herein, the compounds of the invention are useful in thetreatment of various conditions. Thus, in a second aspect, the presentinvention provides a compound of formula I as defined herein for use inmedicine. Preferably the compound is used to prevent or treat conditionswhich require inhibition of potassium channels.

In a further aspect the present invention provides a pharmaceuticalformulation comprising at least one compound of formula I or as definedherein and optionally one or more excepients, carriers or diluents.

The compounds of the invention are found to be inhibitors of voltagegated potassium channels (K_(v)) and are therefore therapeuticallyuseful. Such compounds are believed to be novel and the presentinvention also provides for these compounds. The examples which followare illustrative and, as recognized by one skilled in the art,particular reagents or conditions could be modified as needed forindividual compounds.

Many of the starting materials referred to in the reactions describedabove are available from commercial sources or can be made by methodscited in the literature references.

EXAMPLES

The HPLC analysis was conducted using the following methods:

Solvent: [MeCN-0.05% HCO₂H:H₂O-0.1% HCO₂H], 10-95% gradient 3 mins 95%2.5 min; Column: Phenomenex Gemini 50×4.6 mm id., C18 reverse phase;Flow rate: 0.75 mL/min unless otherwise indicated.

Solvent: [MeCN—H₂O/0.01% HCO₂H], 5-95% gradient 5 min, 95% 3 min Column:Phenomenex Gemini 50×4.6 mm i.d., C18 reverse phase; Flow rate: 1.5mL/min unless otherwise indicated.

Solvent: [MeCN—H₂O/0.01% HCO₂H], 5-95% gradient 3.5 min, 95% 2 minColumn: Phenomenex Gemini 50×3 mm i.d., C18 reverse phase; Flow rate: 1mL/min unless otherwise indicated.

Solvent: [MeCN—H₂O/0.01% HCO₂H], 5-95% gradient 6 min, 95% 3 min Column:Phenomenex Gemini 50×4.6 mm i.d., C18 reverse phase; Flow rate: 1 mL/minunless otherwise indicated.

The preparative HPLC purification was conducted in the following manner:

Solvent: [MeCN-0.05% HCO₂H: H₂O-0.1% HCO₂H], 5-95% gradient 12 min, 95%3 min; Waters X-Bridge 100×19 mm i.d., C18 reverse phase; Flow rate: 16mL/min unless otherwise indicated.

Example 13-[(4-Chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-N-(2-hydroxy-ethyl)-benzamide(Method A) i) 3-(4-Chloro-benzylamino)-benzoic acid tert-butyl ester

A solution of 3-amino-tert-butylbenzoate (2 g, 0.01 mol),4-chlorobenzaldehyde (1.4 g, 0.01 mol) and acetic acid (0.6 ml, 0.01mol) in dichloromethane (80 ml) was stirred for 15 min. Sodiumtriacetoxyborohydride (4.2 g, 0.02 mol) was then added portion-wise over10 min. The mixture was stirred at room temperature for 16 hrs. Water(50 ml) was added and the biphasic mixture stirred for 1 hr. The organiclayer was separated, washed with saturated sodium bicarbonate solution(50 ml), dried over magnesium sulfate and concentrated in vacuo. Theresidue was purified by column chromatography (dichloromethane/petroleumether 80% to 100% v/v) to afford the title compound as a yellow solid(2.3 g). HPLC retention time 3.8 min. Mass spectrum (ES+) m/z 318 (M+H).

The following compounds were synthesised according to the methoddescribed using the appropriate starting materials:

-   5-Benzylamino-2-fluoro-N-isopropyl-benzamide-   3-Benzylamino-benzoic acid tert-butyl ester

The following compounds were synthesised according to the methoddescribed using the appropriate starting materials with the theexception that the reaction was performed in the absence of acetic acid.

-   5-(4-chloro-benzylamino)-2-fluoro-benzoic acid tert-butyl ester

The following compounds were synthesised according to the methoddescribed using the appropriate starling materials with the theexception that sodium borohydride was used as the reducing agent,

-   5-(4-chloro-benzylamino)-2-fluoro-N-isopropyl-benzamide

ii)3-[(4-Chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-benzoicacid tert-butyl ester

A solution of 3-(4-chloro-benzylamino)-benzoic acid tert-butyl ester (1g, 0.03 mol), 1-Methyl-1H-Pyrazole-3-sulfonyl chloride (1.13 g, 0.06mol) and pyridine (0.5 ml 0.06 mol) in dichloromethane (40 ml) wererefluxed for 48 hrs. On cooling, water (50 ml) was added with stirring,the organic layer was separated, dried over magnesium sulfate andconcentrated in vacuo. The residue was purified by column chromatography(ethyl acetate/dichloromethane 0% to 10% v/v) to afford the titlecompound as a clear oil (1.33 g). Mass spectrum (ES+) m/z 49 (M+H).

The following compounds were synthesised according to the methoddescribed using the appropriate starting materials:

-   3-[(4-Chloro-benzyl)-(1-methyl-1H-imidazole-4-sulfonyl)-amino]-benzoic    acid tert-butyl ester-   3-[(4-Chloro-benzyl)-(pyridine-3-sulfonyl)-amino]-benzoic acid    tert-butyl ester-   5-[(4-Chloro-benzyl)-(3-cyano-benzenesulfonyl)-amino]-2-fluoro-benzoic    acid tert-butyl ester-   3-(Benzenesulfonyl-benzyl-amino)-benzoic acid tert-butyl ester-   3-[Benzyl-(1,2-dimethyl-1H-imidazole-4-sulfonyl)-amino]-benzoic acid    tert-butyl ester-   3-[Benzyl-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-benzoic acid    tert-butyl ester-   3-[Benzyl-(1-methyl-1H-imidazole-4-sulfonyl)-amino]-benzoic acid    tert-butyl ester-   3-[Benzyl-(2-fluoro-benzenesulfonyl)-amino]-benzoic acid tert-butyl    ester-   3-[benzyl-(3-fluoro-benzenesulfonyl)-amino]-benzoic acid tert-butyl    ester-   3-[benzyl-(4-fluoro-benzenesulfonyl)-amino]-benzoic acid tert-butyl    ester-   3-(benzyl-methanesulfonyl)-amino)-benzoic acid tert-butyl ester

iii)3-[(4-Chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-benzoicacid

A solution of3-[(4-chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-benzoicacid tert-butyl ester (1.33 g, 0.02 mol) in a mixture of trifluoroaceticacid/dichloromethane (20 ml, 1:1 v/v) was stirred for 3 hrs. Thereaction mixture was concentrated to dryness in vacuo to afford thetitle compound as a white solid (1.37 g). HPLC retention time 2.75 min.Mass spectrum (ES+) m/z 405.9 (M+).

The following compounds were synthesised according to the above methoddescribed using the appropriate starting materials:

-   3-[(4-Chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-benzoic    acid-   3-[(4-Chloro-benzyl)-(pyridine-3-sulfonyl)-amino]-benzoic acid-   5-[(4-Chloro-benzyl)-(3-cyano-benzenesulfonyl)-amino]-2-fluoro-benzoic    acid-   3-(benzenesulfonyl-benzyl-amino)-benzoic acid-   3-[benzyl-(2-fluoro-benzenesulfonyl)-amino]-benzoic acid-   3-[benzyl-(3-fluoro-benzenesulfonyl)-amino]-benzoic acid-   3-[benzyl-(4-fluoro-benzenesulfonyl)-amino]-benzoic acid

The following compounds were synthesised according to the above methoddescribed using the appropriate starting materials with the followingmodifications;

A mixture of trifluoroacetic acid/dichloromethane (12.3 ml, 4:1 v/v) wasused. On evaporation to dryness, the residue was treated with saturatedsodium carbonate solution (50 ml) and partitioned with dichloromethane(50 ml). The basic aqueous solution was collected, acidified to pH 4-5with glacial acetic acid and then extracted using ethyl acetate (2×50ml). The organics were collected, dried over magnesium sulphate andconcentrated to afford the following compounds:

-   3-[Benzyl-(1,2-dimethyl-1H-imidazole-4-sulfonyl)-amino]-benzoic acid-   3-[Benzyl-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-benzoic acid-   3-[Benzyl-(2,4-dimethyl-thiazole-5-sulfonyl)-amino]-benzoic acid-   3-[Benzyl-(1-methyl-1H-imidazole-4-sulfonyl)-amino]-benzoic acid

iv)3-[(4-Chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-N-(2-hydroxy-ethyl)-benzamide(1)

A solution of3-[(4-chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-benzoicacid (30 mg, 0.07 mmol), diisopropylethylamine (0.26 ml, 0.14 mmol),HATU (56 mg, 0.15 mmol) and 2-aminoethanol (9 μL, 0.14 mmol) werestirred in dry acetonitrile (3 ml) for 18 hrs. The reaction mixture wasconcentrated in vacuo and the residue partitioned betweendichloromethane (3 ml) and water (3 ml). The organic layer was separatedand dried by passage through a hydrophobic frit, then concentrated invacuo. The crude residue was purified by preparative HPLC to afford thetitle compound as an off white solid (11.9 mg). HPLC retention time 5.03min. Mass spectrum (ES+) m/z 449 (M+H).

Other compounds prepared by Method A as described, for Example 1 usingthe appropriate starting materials are listed in TABLE 1

Example 2N-Benzyl-3-[benzyl)-(1-methyl-1H-imidazole-4-sulfonyl)-amino]-benzamide(Method B)

3-[Benzyl)-(1-methyl-1H-imidazole-4-sulfonyl)-amino]benzoic acid (50 mg,1.3 mmol), HATU (77 mg, 0.2 mmol), diisopropylethylamine (74 μL, 0.4mmol) and benzylamine (22 μL, 0.2 mmol) were heated in dry acetonitrileunder nitrogen at 60° C. for 18 hrs. After cooling, solvent was removedin vacuo and the residue purified by preparative TLC (100% ethylacetate), to afford the title compound as a colourless oil (4.3 mg).HPLC retention time 5.46 min. Mass spectrum (ES+) m/z 402 (M+H).

Other compounds prepared by Method B as described for Example 2 usingthe appropriate starting materials are listed in TABLE 1

Example 3 3-[Benzyl-(pyridine-3-sulfonyl)-amino]-N-isopropyl-benzamidei) 3-(Pyridine-3-sulfonylamino)-benzoic acid tert-butyl ester

A solution of tert-butyl-3-aminobenzoate (100 mg, 0.5 mmol) andpyridine-3-sulfonylchloride (110 mg, 0.5 mmol) in pyridine (5 ml) washeated to 50° C. for 90 min. On cooling, the reaction was diluted withtoluene (100 ml) and concentrated in vacuo. This was repeated withfurther aliquots of toluene until all the pyridine had been removed toafford the title compound as a yellow oil (175 mg). HPLC retention time4.27 min. Mass spectrum (ES+) m/z 335 (M+H).

ii) 3-[Benzyl-(pyridine-3-sulfonyl)-amino]-benzoic acid

A solution of 3-(Pyridine-3-sulfonylamino)-benzoic acid tert-butyl ester(99 mg, 0.3 mmol), benzyl bromide (39 μL, 0.32 mmol) and CesiumCarbonate (145 mg, 0.4 mmol) in dimethylformamide (5 ml) was stirred for16 hrs. The reaction was diluted with ethyl acetate (50 ml) and washedwith water (6×100 ml). The organic layer was separated, dried overmagnesium sulfate and concentrated in vacuo to give a yellow oil. Theoil was dissolved in trifluoroacetic acid/dichloromethane (1:5 v/v) (10ml), stirred for 3 hrs and then concentrated in vacuo to afford thetitle compound as a white solid (58.7 mg). HPLC retention time 4.31 min.Mass spectrum (APCI+) m/z 369 (M+H).

iii) 3-[Benzyl-(pyridine-3-sulfonyl)-amino]-N-isopropyl-benzamide (3)

3[Benzyl-(pyridine-3-sulfonyl)-amino]-N-isopropyl-benzamide was preparedfrom 3-[benzyl-(pyridine-3-sulfonyl)-amino]-benzoic acid andisopropylamine according to the method described for Example 2. HPLCretention time 5.46 min. Mass spectrum (APCI+) m/z 410 (M+H).

Example 4 3-(Benzenesulfonyl-benzyl-amino)-N-(1H-indazol-6-yl)-benzamide(Method C)

A solution of 3-(benzenesulfonyl-benzyl-amino)-benzoic acid (25 mg,0.068 mmol), 6-amino-1H-indazole (18 mg, 0.136 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (15 mg,0.075 mmol), mercaptobenzothiazole (2 mg, 0.007 mmol) and triethylamine(24 μl, 0.17 mmol) in dry acetonitrile (2 ml) were stirred at roomtemperature for 15 hrs. The reaction mixture was quenched with water (10ml) and extracted with dichloromethane (3×7 ml). The organics werecombined, dried (PTFE frit) and concentrated in vacuo. The crude residuewas purified by preparative TLC (10% diethyl ether in dichloromethane)to afford the title compound as a brown solid (15 mg, 45%). HPLCretention time 5.80 min. Mass spectrum (ES+) m/z 483 (M+H).

Other compounds prepared by Method C as described for Example 4 usingthe appropriate starting materials are listed in TABLE 1

Example 53-[(4-Acetylamino-benzenesulfonyl)-benzyl-amino]-N-isopropyl-benzamide(Method D) i) 3-Benzylamino-benzoic acid

A solution of 3-benzylamino-benzoic acid tert-butyl ester (1 g, 3 mmol)in trifluoroacetic acid/dichloromethane (1:5 v/v) (100 ml) was stirredfor 16 hrs. The reaction was concentrated to dryness in vacuo to affordthe title compound as a white solid. HPLC retention time 2.59 min. Massspectrum (ES+) m/z 227.8 (M+).

The following compound was synthesised according to the above methoddescribed using the appropriate starting materials:

-   3-(4-Chloro-benzylamino)-benzoic acid

ii) 3-Benzylamino)-N-isopropanyl-benzamide

A solution of 3-benzylamino-benzoic acid (500 mg, 1.5 mmol), HATU (832mg, 2 mmol), diisopropylethylamine (0.38 ml, 2 mmol) and isopropylamine(0.19 ml, 2 mmol) in acetonitrile was heated to 50° C. for 16 hrs. Oncooling, solvents were removed in vacuo and the residue partitionedbetween dichloromethane and water (50 ml/50 ml). The organic layer wasseparated, dried over magnesium sulfate and concentrated in vacuo. Theresidue was purified by column chromatography (ethylacetate/dichloromethane 0% to 50% v/v) to afford the title compound as awhite solid (242 mg). HPLC retention time 2.69 min. Mass spectrum (EST+)m/z 269.9 (M+H).

The following compound was synthesised according to the above methoddescribed using the appropriate starting materials:

-   3-(4-Chloro-benzylamino)-N-isopropyl-benzamide

iii)3-[(4-Acetylamino-benzenesulfonyl)-benzyl-amino]-N-isopropyl-benzamide(5)

3-Benzenesulfonyl-N-isopropyl-benzamide (20 mg, 0.07 mmol), pyridine (18μL, 0.2 mmol) and 4-acetylamidobenzenesulfonyl chloride (50 mg, 0.2mmol) were refluxed in dry dichloromethane for 18 hrs. On cooling,solvents were removed in vacuo and the residue purified by preparativeLCMS to afford an off-white solid (0.5 mg). HPLC retention time 4.09min. Mass spectrum (ES+) m/z 466 (M+H).

Other compounds prepared by Method D as described for Example 5 usingthe appropriate starting materials are listed in TABLE 1

Example 65-[(Benzyl-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-sulfonyl)-amino]-2-fluoro-N-isopropyl-benzamide(Method E) i) 5-Amino-2-fluoro-N-isopropyl-benzamide

A solution of 5-amino-2-fluorobenzoic acid (300 mg, 1.9 mmol),diisopropylethylamine (1 ml, 5.8 mmol), and isopropylamine (0.3 ml, 3.9mmol) in acetonitrile was heated to 110° C. in microwave for 45 min.This reaction was repeated 5 times and the crude products combined thenconcentrated in vacuo. The residue was purified by flash chromatography(SiO₂) eluting with ethyl acetate/dichloromethane (0% to 10% v/v) toafford the title compound as a yellow solid (2.31 g). HPLC retentiontime 3.93 min. Mass spectrum ES+) m/z 197 (M+H).

ii) 5-Benzylamino-2-fluoro-N-isopropyl-benzamide

5-Benzylamino-2-fluoro-N-isopropyl-benzamide was synthesized from5-amino-2-fluoro-N-isopropyl-benzamide and benzaldehyde according to themethod described in Example 1

iii)5-[Benzyl-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-sulfonyl)-amino]-2-fluoro-N-isopropyl-benzamide(6)

A solution of 5-benzylamino-2-fluoro-N-isopropyl-benzamide (30 mg, 0.1mmol), diisopropylethylamine (37 μL, 0.2 mmol), and3-oxo-3,4-dihydro-2H-1,4-benzooxazine-6-sulfonyl chloride (52 mg, 0.2mmol) was refluxed in dry dichloromethane (3 ml) for 18 hrs. On cooling,water (10 ml) was added with stirring. The organic layer was separated,dried (PTFE frit), then concentrated in vacuo. The crude residue waspurified by preparative TLC (10% v/v ethyl acetate/dichloromethane) toafford the title compound as an off white solid (23 mg). HPLC retentiontime 7.72 min. Mass spectrum (ES+) m/z 499 (M+H).

Other compounds prepared by Method E as described for Example 6 usingthe appropriate starting materials are listed in TABLE 1

Example 73-[(4-Chloro-benzyl-(2-methyl-2H-pyrazole-3-sulfonyl)-amino]-N-isopropyl-benzamide(Method F)

3-(4-Chloro-benzylamino-N-isopropyl-benzamide (30 mg, 0.1 mmol),diisopropylethylamine (35 μL, 0.2 mmol) and1-methyl-1H-pyrazole-5-sulfonyl chloride (36 mg, 0.2 mmol) were stirredin dry dichloromethane (2 ml) at room temperature for 72 hrs. Thereaction was diluted with dichloromethane (5 ml) and water (5 ml) withstirring. The organics were collected, dried (PTFE frit) andconcentrated in vacuo. The residue was purified by preparative TLC (10%ethyl acetate/dichloromethane) to yield the product as an off-whitesolid (11.9 mg). HPLC retention time 8.04 min. Mass spectrum (ES+) m/z44 (M+H).

Other compounds prepared by Method F as described for Example 7 usingthe appropriate starting materials are listed in TABLE 1

TABLE 1 Summary of synthesis methods and characterisation data LCMS(ES+) Ret.n m/z Example Name Method time (M + H) 13-[(4-Chloro-benzyl)-(1-methyl-1H- A 5.0 449pyrazole-3-sulfonyl)-amino]-N-(2- hydroxy-ethyl)-benzamide 2N-Benzyl-3-[benzyl-(1-methyl-1H- B 5.5 462 imidazole-4-sulfonyl)-amino]-benzamide 3 3-[Benzyl-(pyridine-3-sulfonyl)- B 5.5 410amino]-N-isopropyl-benzamide 4 3-(Benzenesulfonyl-benzyl-amino)-N- C 5.8483 (1H-indazol-6-yl)-benzamide 5 3-[(4-Acetylamino-benzenesulfonyl)- D4.1 466 benzyl-amino]-N-isopropyl-benzamide 65-[Benzyl-(3-oxo-3,4-dihydro-2H- E 7.7 499benzo[1,4]oxazine-6-sulfonyl)-amino]- 2-fluoro-N-isopropyl-benzamide 73-[(4-Chloro-benzyl)-(2-methyl-2H- F 8.0 447pyrazole-3-sulfonyl)-amino]-N- isopropyl-benzamide 83-(Benzenesulfonyl-benzyl-amino)-N- B 4.7 457 benzyl-benzamide 93-(Benzenesulfonyl-benzyl-amino)-N- B 4.5 409 isopropyl-benzamide 103-(Benzenesulfonyl-benzyl-amino)-N- B 4.7 471 phenethyl-benzamide 11N-Benzyl-N-[3-(4-phenyl-piperidine-1- B 4.9 511carbonyl)-phenyl]-benzenesulfonamide 12N-Benzyl-N-[3-(3-phenyl-piperidine-1- B 5.0 511carbonyl)-phenyl]-benzenesulfonamide 13N-Benzyl-N-[3-(2-phenyl-morpholine- B 5.0 513 4-carbonyl)-phenyl]-benzenesulfonamide 14 N-Benzyl-N-[3-(4-phenoxy-piperidine- B 5.4 5271-carbonyl)-phenyl]- benzenesulfonamide 153-(Benzenesulfonyl-benzyl-amino)-N- B 5.6 484(3-phenyl-propyl)-benzamide 16 3-(Benzenesulfonyl-benzyl-amino)-N- B 4.2381 methyl-benzamide 17 3-(benzenesulfonyl-benzyl-amino)-N- C 7.5 423tert-butyl-benzamide 18 N-benzyl-N-[3-(3-phenyl-piperidine-1- C 7.1 449carbonyl)-phenyl]-methanesulfonamide 19N-benzyl-N-[3-(2-phenyl-morpholine- C 6.7 451 4-carbonyl)-phenyl]-methanesulfonamide 20 N-benzyl-N-[3-(4-phenoxy-piperidine- C 6.9 4651-carbonyl)-phenyl]- methanesulfonamide 21N-benzyl-N-[3-(4-phenyl-piperidine-1- C 7.1 449carbonyl)-phenyl]-methanesulfonamide 22 1-Methyl-1H-imidazole-4-sulfonicacid B 5.9 515 benzyl-[3-(4-phenyl-piperidine-1- carbonyl)-phenyl]-amide23 N-Benzyl-N-[3-(morpholine-4- B 5.7 437carbonyl)-phenyl]-benzenesulfonamide 243-(benzenesulfonyl-benzyl-amino)-N- C 5.6 445pyridin-2-ylmethyl-benzamide 25 3-(benzenesulfonyl-benzyl-amino)-N- C5.7 483 (1H-indazol-5-yl)-benzamide 263-(benzenesulfonyl-benzyl-amino)-N- C 5.8 509(4-imidazol-1-yl-phenyl)-benzamide 273-(benzenesulfonyl-benzyl-amino)-N- C 6.3 509(4-pyrazol-1-yl-phenyl)-benzamide 28 3-(benzenesulfonyl-benzyl-amino)-N-C 5.7 451 [1,3,4]thiadiazol-2-yl-benzamide 293-(benzenesulfonyl-benzyl-amino)-N- C 6.1 450 thiazol-2-yl-benzamide 30N-[4-(aminocarbonyl)phenyl]-3- C 5.5 503[benzyl(phenylsulfonyl)amino]benzamide NH₃ salt 31N-[3-(aminocarbonyl)phenyl]-3- C 5.5 503[benzyl(phenylsulfonyl)amino]benzamide NH₃ salt 323-(benzenesulfonyl-benzyl-amino)-N- C 6.4 443 phenyl-benzamide 331-Methyl-1H-imidazole-4-sulfonic acid B 5.6 517benzyl-[3-(2-phenyl-morpholine-4- carbonyl)-phenyl]-amide 343-[Benzyl-(1,2-dimethyl-1H-imidazole B 5.1 4274-sulfonyl)-amino]-N-isopropyl- benzamide 353-[Benzyl-(1-methyl-1H-pyrazole-3- B 5.4 413sulfonyl)-amino]-N-isopropyl- benzamide 363-[Benzyl-(2,4-dimethyl-thiazole-5- B 5.8 444sulfonyl)-amino]-N-isopropyl- benzamide 37N-benzyl-2-fluoro-N-[3-(morpholine-4- C 5.7 455carbonyl)-phenyl]-benzenesulfonamide 383-[benzyl-(2-fluoro-benzenesulfonyl)- C 5.8 413amino]-N,N-dimethyl-benzamide 39 3-[benzyl-(3-fluoro-benzenesulfonyl)- C5.8 413 amino]-N,N-dimethyl-benzamide 40N-benzyl-4-fluoro-N-[3-(morpholine-4- C 5.8 455carbonyl)-phenyl]-benzenesulfonamide 413-[benzyl-(4-fluoro-benzenesulfonyl)- C 5.8 413amino]-N,N-dimethyl-benzamide 42 3-[benzyl-(4-fluoro-benzenesulfonyl)- C8.0 427 amino]-N-isopropyl-benzamide 43 1-Methyl-1H-imidazole-4-sulfonicacid B 4.1 534 benzyl-{3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-phenyl}-amide 443-[benzyl-(2-fluoro-benzenesulfonyl)- C 6.0 427amino]-N-isopropyl-benzamide 45 3-[benzyl-(3-fluoro-benzenesulfonyl)- C6.1 427 amino]-N-isopropyl-benzamide 46 1-Methyl-1H-imidazole-4-sulfonicacid B 2.8 536 benzyl-[3-(4-cyclohexylmethyl-piperazine-1-carbonyl)-phenyl]-amide 473-[Benzyl-(2,3-dihydro-benzofuran-5- D 4.6 451sulfonyl)-amino]-N-isopropyl- benzamide 483-[Benzyl-(2,2-dimethyl-chroman-6- D 5.2 493sulfonyl)-amino]-N-isopropyl- benzamide 49 3-[Benzyl-(2,3-dihydro- D 4.6467 benzo[1,4]dioxine-6-sulfonyl)-amino]- N-isopropyl-benzamide 503-[(1-Acetyl-2,3-dihydro-1H-indole-5- D 4.4 492sulfonyl)-benzyl-amino]-N-isopropyl- benzamide 513-[Benzyl-(2-methyl-2H-pyrazole-3- D 4.4 413sulfonyl)-amino]-N-isopropyl- benzamide 523-[Benzyl-(4-methyl-3,4-dihydro-2H- D 4.7 480benzo[1,4]oxazine-7-sulfonyl)-amino]- N-isopropyl-benzamide 533-[Benzyl-(3-oxo-3,4-dihydro-2H- D 4.3 480benzo[1,4]oxazine-6-sulfonyl)-amino]- N-isopropyl-benzamide 542,3-Dihydro-benzo[1,4]dioxine-6- D 4.5 495 sulfonic acidbenzyl-[3-(morpholine-4- carbonyl)-phenyl]-amide 554-Methyl-3,4-dihydro-2H- D 4.5 508 benzo[1,4]oxazine-7-sulfonic acidbenzyl-[3-(morpholine-4-carbonyl)- phenyl]-amide 56Benzo[1,2,5]oxadiazole-4-sulfonic acid D 4.7 479benzyl-[3-(morpholine-4-carbonyl)- phenyl]-amide 57Benzo[1,3]dioxole-5-sulfonic acid benzyl- D 4.7 481[3-(morpholine-4-carbonyl)-phenyl]- amide 583-(Benzenesulfonyl-benzyl-amino)-N- B 4.4 407 cyclopropyl-benzamide 593-(Benzenesulfonyl-benzyl-amino)-N- B 4.6 421 cyclobutyl-benzamide 603-(Benzenesulfonyl-benzyl-amino)-N- B 4.8 435 cyclopentyl-benzamide 613-(Benzenesulfonyl-benzyl-amino)-N- B 4.3 439(2-hydroxy-1,1-dimethyl-ethyl)- benzamide 623-(Benzenesulfonyl-benzyl-amino)-N- B 4.0 425(2-hydroxy-1-methyl-ethyl)-benzamide 633-(Benzenesulfonyl-benzyl-amino)-N- B 4.1 439(1-hydroxymethyl-propyl)-benzamide 643-(Benzenesulfonyl-benzyl-amino)-N- B 3.9 425(2-hydroxy-propyl)-benzamide 65 3-(Benzenesulfonyl-benzyl-amino)-N- B4.8 423 isobutyl-benzamide 66 3-(Benzenesulfonyl-benzyl-amino)-N- B 4.3395 ethyl-benzamide 67 3-(Benzenesulfonyl-benzyl-amino)-N- B 4.2 425(2-methoxy-ethyl)-benzamide 68 3-(Benzenesulfonyl-benzyl-amino)-N- B 3.8411 (2-hydroxy-ethyl)-benzamide 69 3-(Benzenesulfonyl-benzyl-amino)-N- B4.6 409 propyl-benzamide 70 3-(Benzenesulfonyl-benzyl-amino)-N- B 3.9425 (3-hydroxy-propyl)-benzamide 71 3-(Benzenesulfonyl-benzyl-amino)-N-B 4.0 439 (4-hydroxy-butyl)-benzamide 723-(Benzenesulfonyl-benzyl-amino)-N- B 4.6 421cyclopropylmethyl-benzamide 73 3-(Benzenesulfonyl-benzyl-amino)-N- B 3.6441 (2-hydroxy-1-hydroxymethyl-ethyl)- benzamide 743-(Benzenesulfonyl-benzyl-amino)-N- B 4.2 439((R)-1-hydroxymethyl-propyl)- benzamide 75 5-[(Benzo[1,2,5]oxadiazole-4-E 4.3 469 sulfonyl)-benzyl-amino]-2-fluoro-N- isopropyl-benzamide 765-(Benzenesulfonyl-benzyl-amino)-2- E 4.3 427fluoro-N-isopropyl-benzamide 77 5-[Benzyl-(1-methyl-1H-imidazole-4- E7.3 431 sulfonyl)-amino]-2-fluoro-N-isopropyl- benzamide 785-[Benzyl-(4-fluoro-benzenesulfonyl)- E 4.4 445amino]-2-fluoro-N-isopropyl- benzamide 79 5-[Benzyl-(2,3-dihydro- E 4.3485 benzo[1,4]dioxine-6-sulfonyl)-amino]- 2-fluoro-N-isopropyl-benzamide80 5-[Benzyl-(4-cyano-benzenesulfonyl)- E 4.3 452amino]-2-fluoro-N-isopropyl- benzamide 815-[Benzyl-(3-cyano-benzenesulfonyl)- E 4.3 452amino]-2-fluoro-N-isopropyl- benzamide 825-[Benzyl-(2-cyano-benzenesulfonyl)- E 4.2 452amino]-2-fluoro-N-isopropyl- benzamide 835-[(Benzo[1,3]dioxole-5-sulfonyl)- E 4.3 471benzyl-amino]-2-fluoro-N-isopropyl- benzamide 845-[Benzyl-(2,3-dihydro-benzofuran-5- E 4.7 469sulfonyl)-amino]-2-fluoro-N-isopropyl- benzamide 855-[Benzyl-(pyridine-3-sulfonyl)- E 3.8 428 amino]-2-fluoro-N-isopropyl-benzamide 86 5-[(4-Acetylamino-benzenesulfonyl)- E 3.9 484benzyl-amino]-2-fluoro-N-isopropyl- benzamide 873-[(4-Chloro-benzyl)-(pyridine-3- E 7.9 444sulfonyl)-amino]-N-isopropyl- benzamide 883-[(4-Chloro-benzyl)-(3-oxo-3,4- F 7.8 514dihydro-2H-benzo[1,4]oxazine-6- sulfonyl)-amino]-N-isopropyl- benzamide89 3-[(4-Chloro-benzyl)-(1-methyl-1H- E 7.8 447pyrazole-3-sulfonyl)-amino]-N- isopropyl-benzamide 903-[(4-Chloro-benzyl)-(1-methyl-1H- E 7.9 447imidazole-4-sulfonyl)-amino]-N- isopropyl-benzamide 915-[Benzyl-(1-methyl-1H-pyrazole-3- E 7.7 431sulfonyl)-amino]-2-fluoro-N-isopropyl- benzamide 923-[(4-Chloro-benzyl)-(4-methyl-3,4- F 8.4 514dihydro-2H-benzo[1,4]oxazine-6- sulfonyl)-amino]-N-isopropyl- benzamide93 3-[(4-Chloro-benzyl)-(1,2-dimethyl- F 7.5 4611H-imidazole-4-sulfonyl)-amino]-N- isopropyl-benzamide 945-[Benzyl-(1,2-dimethyl-1H-imidazole- E 7.3 4454-sulfonyl)-amino]-2-fluoro-N- isopropyl-benzamide 955-[Benzyl-(2-methyl-2H-pyrazole-3- E 7.9 431sulfonyl)-amino]-2-fluoro-N-isopropyl- benzamide 965-[(4-chloro-benzyl)-(pyridine-3- D 8.1 464sulfonyl)-amino]-2-fluoro-N-isopropyl- benzamide 975-[(4-chloro-benzyl)-(1-methyl-1H- D 8.0 465pyrazole-3-sulfonyl)-amino]-2-fluoro- N-isopropyl-benzamide 985-[(4-chloro-benzyl)-(2-methyl-2H- D 8.2 465pyrazole-3-sulfonyl)-amino]-2-fluoro- N-isopropyl-benzamide 995-[(4-chloro-benzyl)-(1,2-dimethyl-1H- D 7.7 479imidazole-4-sulfonyl)-amino]-2-fluoro- N-isopropyl-benzamide 1005-[(4-chloro-benzyl)-(1-methyl-1H- D 7.9 465pyrazole-4-sulfonyl)-amino]-2-fluoro- N-isopropyl-benzamide 1015-[(4-Chloro-benzyl)-(3-cyano- A 7.6 488benzenesulfonyl)-amino]-2-fluoro-N- (2-hydroxy-ethyl)-benzamide 1025-[(4-Chloro-benzyl)-(3-cyano- A 7.9 516benzenesulfonyl)-amino]-2-fluoro-N- (1-hydroxymethyl-propyl)-benzamide103 N-(4-Chloro-benzyl)-3-cyano-N-[4- A 7.6 500fluoro-3-(3-hydroxy-azetidine-1- carbonyl)-phenyl]-benzenesulfonamide104 5-[(4-Chloro-benzyl)-(3-cyano- A 7.4 518benzenesulfonyl)-amino]-2-fluoro-N- (2-hydroxy-1-hydroxymethyl-ethyl)-benzamide 105 5-[(4-Chloro-benzyl)-(3-cyano- A 7.7 502benzenesulfonyl)-amino]-2-fluoro-N- (2-hydroxy-1-methyl-ethyl)-benzamide106 5-[(4-Chloro-benzyl)-(3-cyano- A 8.0 516benzenesulfonyl)-amino]-2-fluoro-N- (2-hydroxy-1,1-dimethyl-ethyl)-benzamide 107 5-[(4-Chloro-benzyl)-(3-cyano- A 8.0 502benzenesulfonyl)-amino]-2-fluoro-N- (2-methoxy-ethyl)-benzamide 108N-(4-Chloro-benzyl)-3-cyano-N-[4- A 7.8 528fluoro-3-(3-hydroxy-piperidine-1- carbonyl)-phenyl]-benzenesulfonamide109 N-(4-Chloro-benzyl)-3-cyano-N-[4- A 7.6 514fluoro-3-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-phenyl]-benzenesulfonamide 1103-[(4-Chloro-benzyl)-(pyridine-3-sulfonyl)- A 7.0 446amino]-N-(2-hydroxy-ethyl)- benzamide 1113-[(4-Chloro-benzyl)-(pyridine-3- A 7.1 460sulfonyl)-amino]-N-(2-hydroxy-1- methyl-ethyl)-benzamide 1123-[(4-Chloro-benzyl)-(pyridine-3- A 7.4 474sulfonyl)-amino]-N-(1-hydroxymethyl- propyl)-benzamide 113Pyridine-3-sulfonic acid (4-chloro- A 7.0 458benzyl)-[3-(3-hydroxy-azetidine-1- carbonyl)-phenyl]-amide 114Pyridine-3-sulfonic acid (4-chloro- A 7.3 486benzyl)-[3-(3-hydroxy-piperidine-1- carbonyl)-phenyl]-amide 1153-[(4-Chloro-benzyl)-(pyridine-3- A 7.5 474sulfonyl)-amino]-N-(2-hydroxy-1,1- dimethyl-ethyl)-benzamide 1163-[(4-Chloro-benzyl)-(pyridine-3- A 7.5 460sulfonyl)-amino]-N-(2-methoxy-ethyl)- benzamide 1173-[(4-Chloro-benzyl)-(pyridine-3- A 7.7 442sulfonyl)-amino]-N-cyclopropyl- benzamide 1183-[(4-Chloro-benzyl)-(pyridine-3- A 8.1 470sulfonyl)-amino]-N-cyclopentyl- benzamide 119 Pyridine-3-sulfonic acid(4-chloro- A 7.6 474 benzyl)-[3-((R)-3-fluoro-pyrrolidine-1-carbonyl)-phenyl]-amide 120 3-[(4-Chloro-benzyl)-(pyridine-3- A 8.0 456sulfonyl)-amino]-N-cyclobutyl- benzamide 121 Pyridine-3-sulfonic acid[3-(azetidine- A 7.6 442 1-carbonyl)-phenyl]-(4-chloro-benzyl)- amide122 3-[(4-Chloro-benzyl)-(1-methyl-1H- A 7.1 419imidazole-4-sulfonyl)-amino]-N- methyl-benzamide 1233-[(4-Chloro-benzyl)-(1-methyl-1H- A 7.3 433imidazole-4-sulfonyl)-amino]-N-ethyl- benzamide 1243-[(4-Chloro-benzyl)-(1-methyl-1H- A 7.2 463imidazole-4-sulfonyl)-amino]-N-(2- methoxy-ethyl)-benzamide 1253-[(4-Chloro-benzyl)-(1-methyl-1H- A 7.3 445imidazole-4-sulfonyl)-amino]-N- cyclopropyl-benzamide 1263-[(4-Chloro-benzyl)-(1-methyl-1H- A 7.8 473imidazole-4-sulfonyl)-amino]-N- cyclopentyl-benzamide 1273-[(4-Chloro-benzyl)-(1-methyl-1H- A 8.4 459imidazole-4-sulfonyl)-amino]-N- cyclobutyl-benzamide 1281-Methyl-1H-imidazole-4-sulfonic acid A 7.2 445[3-(azetidine-1-carbonyl)-phenyl]-(4- chloro-benzyl)-amide 1293-[(4-Chloro-benzyl)-(1-methyl-1H- A 5.4 419pyrazole-3-sulfonyl)-amino]-N-methyl- benzamide 1303-[(4-Chloro-benzyl)-(1-methyl-1H- A 5.6 433pyrazole-3-sulfonyl)-amino]-N-ethyl- benzamide 1313-[(4-Chloro-benzyl)-(1-methyl-1H- A 5.4 463pyrazole-3-sulfonyl)-amino]-N-(2- methoxy-ethyl)-benzamide 1323-[(4-Chloro-benzyl)-(1-methyl-1H- A 5.6 445pyrazole-3-sulfonyl)-amino]-N- cyclopropyl-benzamide 1333-[(4-Chloro-benzyl)-(1-methyl-1H- A 5.9 459pyrazole-3-sulfonyl)-amino]-N- cyclobutyl-benzamide 1341-Methyl-1H-pyrazole-3-sulfonic acid A 5.5 445[3-(azetidine-1-carbonyl)-phenyl]-(4- chloro-benzyl)-amide 1351-Methyl-1H-pyrazole-3-sulfonic acid A 6.2 487(4-chloro-benzyl)-[3-(3-methyl- piperidine-1-carbonyl)-phenyl]-amide 1363-[(4-Chloro-benzyl)-(1-methyl-1H- A 6.0 473pyrazole-3-sulfonyl)-amino]-N- cyclopentyl-benzamide 1373-[(4-Chloro-benzyl)-(1-methyl-1H- A 5.2 463pyrazole-3-sulfonyl)-amino]-N-(2- hydroxy-1-methyl-ethyl)-benzamide 1383-[(4-Chloro-benzyl)-(1-methyl-1H- A 5.3 477pyrazole-3-sulfonyl)-amino]-N-(1- hydroxymethyl-propyl)-benzamide 1393-[(4-Chloro-benzyl)-(1-methyl-1H- A 5.5 477pyrazole-3-sulfonyl)-amino]-N-(2- hydroxy-1,1-dimethyl-ethyl)- benzamide140 3-[(4-chloro-benzyl)-(2-methyl-2H- B 6.1 459pyrazole-3-sulfonyl)-amino]-N- cyclobutyl-benzamide 1413-[(4-chloro-benzyl)-(2-methyl-2H- B 9.3 473pyrazole-3-sulfonyl)-amino]-N- cyclopentyl-benzamide

Example 142 Kv1.3 Autopatch Electrophysiology Method

Cells stably transfected with cDNA for human Kv1.3 (In pcDNA3.1) weregrown in Ex-cell 302 serum-free medium for CHO cells, supplemented with10 μl/ml [100×] glutamine, 500 μg/ml G418 (gentimicin), and 1% HTsupplement (50×, hypoxanthine and thymidine). Compounds were tested onthese cells using the AutoPatch technology in whole cell mode.

The external bathing solution contained (in mM): 150 NaCl, 10 KCl, 1MgCl₂, 3 CaCl₂, 10 HEPES, pH 7.4 with NaOH. Patch pipettes were filledwith an electrode solution of composition (in mM): 100 K-Gluconate, 20KCl, 1 MgCl₂, 1 CaCl₂, 10 HEPES, 11 EGTA, 5 ATP-Na₂, 2 Glutathione pH7.2 with KOH.

Compounds were dissolved in DMSO (100%) and made up in the externalbather at a concentration of 1 μM immediately prior to use. Allexperiments were conducted at room temperature.

A cell suspension (10 ml), with a density of 6×10⁶ cells, was aliquotedinto a 15 ml centrifuge tube and stored at 4° C. before use. Prior touse a tube was taken and centrifuged at 1000 rpm for 4 mins at roomtemperature. The supernatant was then discarded, leaving a cell pelletat the bottom of the tube. The pellet was then resuspended using 1 ml ofcold (4° C.), filtered (0.22 μm), 0.05% BSA/bather solution (0.05 gBSA/100 ml bather). The bottom of the tube was manually agitatedfollowed by gentle tituration. The cell suspension was then placed inthe AutoPatch™ temperature controlled cell-hotel at 14° C. and regularlytiturated.

A length of Teflon capillary tubing was dipped into the cell suspensionsolution, and a column of fluid was taken up by negative pressure. Thecolumn of fluid was in electrically connectivity with a Ag/AgClreference electrode. Borosilicate glass patch pipettes (from 1.5 mm OD,thin-walled filamented, GC150-TF capillary glass, Harvard) were pulledusing a DMZ pipette puller (Zeitz Instruments), and were back-filledusing the internal pipette solution, being careful that no bubblesremained at the tip or in the body of the pipette. Patch pipettestypically had resistances of 2.5-3.5 MΩ. Once filled, the pipette tipand a proportion of the shaft (˜15 mm) were dipped into Sigmacote(Sigma). The recording pipettes were placed in a multiwell array andmounted on the AutoPatch™ machine. Automated patch-clamping anddrug-application was initiated by the operator, but thereafterAutoPatch.exe continued the experiment providing that pre-set conditionsand criteria were satisfied.

Whole cell patch-clamp recordings were made using the AutoPatch™ rig,which incorporated an EPC9 or EPC10 amplifier (HEKA, Germany) undercontrol of Pulse software (v8.54 or v8.76, HEKA, Germany), a cellapplicator, automated drug application system (DAS), valve controller(VF1) and a suction device all at room temperature. This equipment wascompletely under the control of AutoPatch.exe and operator interventionwas only made when there was a requirement to refill the batherreservoirs or to prevent the loss of a cell due to a technical error.

Qualification stages prior to perfusion and drug application ensuredthat the observed current met the criteria for the experiment. Cellswere continuously perfused with external solution at a flow rate of ˜2ml/minute. The perfusion chamber had a working volume of 80-85 μl thatallowed for rapid exchange of drug solutions.

Electrophysiology voltage-step protocols and analysis of data wasperformed as follows. Data were sampled at 5 kHz, and filtered with a −3dB bandwidth of 2.5 kHz. Cells were held at a voltage of −80 mV.Currents were evoked by a voltage step to +30 mV for 500 ms in durationapplied every 15 s. Online analysis of the hKv1.3 current during theapplication of compounds was performed by the Pulse (v8.54 or V8.76,HEKA, Germany), Excel (Microsoft, USA) and AutoPatch™ software, with thetotal charge measured during the whole of voltage step. Inhibition ofcharge movement in the presence of drug was calculated relative tocontrol.

Example 143 Summary of Kv1.3 Biological Activity

hKv1.3 Example Name % inh. 1 3-[(4-Chloro-benzyl)-(1-methyl-1H- 86pyrazole-3-sulfonyl)-amino]-N-(2- hydroxy-ethyl)-benzamide 2N-Benzyl-3-[benzyl-(1-methyl-1H- 69 imidazole-4-sulfonyl)-amino]-benzamide 3 3-[Benzyl-(pyridine-3-sulfonyl)- 92amino]-N-isopropyl-benzamide 4 3-(Benzenesulfonyl-benzyl-amino)-N- 88(1H-indazol-6-yl)-benzamide 5 3-[(4-Acetylamino-benzenesulfonyl)- 45benzyl-amino]-N-isopropyl-benzamide 6 5-[Benzyl-(3-oxo-3,4-dihydro-2H-84 benzo[1,4]oxazine-6-sulfonyl)-amino]- 2-fluoro-N-isopropyl-benzamide7 3-[(4-Chloro-benzyl)-(2-methyl-2H- 57 pyrazole-3-sulfonyl)-amino]-N-isopropyl-benzamide 10 3-(Benzenesulfonyl-benzyl-amino)-N- 94benzyl-benzamide 11 3-(Benzenesulfonyl-benzyl-amino)-N- 89isopropyl-benzamide 12 3-(Benzenesulfonyl-benzyl-amino)-N- 100phenethyl-benzamide 13 N-Benzyl-N-[3-(4-phenyl-piperidine-1- 97carbonyl)-phenyl]-benzenesulfonamide 14N-Benzyl-N-[3-(3-phenyl-piperidine-1- 74carbonyl)-phenyl]-benzenesulfonamide 15N-Benzyl-N-[3-(2-phenyl-morpholine- 91 4-carbonyl)-phenyl]-benzenesulfonamide 16 N-Benzyl-N-[3-(4-phenoxy-piperidine- 971-carbonyl)-phenyl]- benzenesulfonamide 173-(Benzenesulfonyl-benzyl-amino)-N- 97 (3-phenyl-propyl)-benzamide 183-(Benzenesulfonyl-benzyl-amino)-N- 74 methyl-benzamide 193-(benzenesulfonyl-benzyl-amino)-N- 89 tert-butyl-benzamide 20N-benzyl-N-[3-(3-phenyl-piperidine-1- 89carbonyl)-phenyl]-methanesulfonamide 21N-benzyl-N-[3-(2-phenyl-morpholine- 47 4-carbonyl)-phenyl]-methanesulfonamide 22 N-benzyl-N-[3-(4-phenoxy-piperidine- 631-carbonyl)-phenyl]- methanesulfonamide 23N-benzyl-N-[3-(4-phenyl-piperidine-1- 62carbonyl)-phenyl]-methanesulfonamide 24 1-Methyl-1H-imidazole-4-sulfonicacid 61 benzyl-[3-(4-phenyl-piperidine-1- carbonyl)-phenyl]-amide 25N-Benzyl-N-[3-(morpholine-4- 66 carbonyl)-phenyl]-benzenesulfonamide 263-(benzenesulfonyl-benzyl-amino)-N- 79 pyridin-2-ylmethyl-benzamide 273-(benzenesulfonyl-benzyl-amino)-N- 95 (1H-indazol-5-yl)-benzamide 283-(benzenesulfonyl-benzyl-amino)-N- 98(4-imidazol-1-yl-phenyl)-benzamide 293-(benzenesulfonyl-benzyl-amino)-N- 99 (4-pyrazol-1-yl-phenyl)-benzamide30 3-(benzenesulfonyl-benzyl-amino)-N- 95[1,3,4]thiadiazol-2-yl-benzamide 31 3-(benzenesulfonyl-benzyl-amino)-N-93 thiazol-2-yl-benzamide 32 N-[4-(aminocarbonyl)phenyl]-3- 95[benzyl(phenylsulfonyl)amino]benzamide 33 N-[3-(aminocarbonyl)phenyl]-3-92 [benzyl(phenylsulfonyl)amino]benzamide 343-(benzenesulfonyl-benzyl-amino)-N- 91 phenyl-benzamide 351-Methyl-1H-imidazole-4-sulfonic acid 75benzyl-[3-(2-phenyl-morpholine-4- carbonyl)-phenyl]-amide 363-[Benzyl-(1,2-dimethyl-1H-imidazole- 88 4-sulfonyl)-amino]-N-isopropyl-benzamide 37 3-[Benzyl-(1-methyl-1H-pyrazole-3- 83sulfonyl)-amino]-N-isopropyl- benzamide 383-[Benzyl-(2,4-dimethyl-thiazole-5- 50 sulfonyl)-amino]-N-isopropyl-benzamide 39 N-benzyl-2-fluoro-N-[3-(morpholine-4- 58carbonyl)-phenyl]-benzenesulfonamide 403-[benzyl-(2-fluoro-benzenesulfonyl)- 47 amino]-N,N-dimethyl-benzamide41 3-[benzyl-(3-fluoro-benzenesulfonyl)- 41amino]-N,N-dimethyl-benzamide 42 N-benzyl-4-fluoro-N-[3-(morpholine-4-61 carbonyl)-phenyl]-benzenesulfonamide 433-[benzyl-(4-fluoro-benzenesulfonyl)- 77 amino]-N,N-dimethyl-benzamide44 3-[benzyl-(4-fluoro-benzenesulfonyl)- 90 amino]-N-isopropyl-benzamide45 1-Methyl-1H-imidazole-4-sulfonic acid 53benzyl-{3-[4-(2-fluoro-phenyl)- piperazine-1-carbonyl]-phenyl}-amide 463-[benzyl-(2-fluoro-benzenesulfonyl)- 74 amino]-N-isopropyl-benzamide 473-[benzyl-(3-fluoro-benzenesulfonyl)- 76 amino]-N-isopropyl-benzamide 481-Methyl-1H-imidazole-4-sulfonic acid 59 benzyl-[3-(4-cyclohexylmethyl-piperazine-1-carbonyl)-phenyl]-amide 493-[Benzyl-(2,3-dihydro-benzofuran-5- 99 sulfonyl)-amino]-N-isopropyl-benzamide 50 3-[Benzyl-(2,2-dimethyl-chroman-6- 92sulfonyl)-amino]-N-isopropyl- benzamide 51 3-[Benzyl-(2,3-dihydro- 97benzo[1,4]dioxine-6-sulfonyl)-amino]- N-isopropyl-benzamide 523-[(1-Acetyl-2,3-dihydro-1H-indole-5- 78sulfonyl)-benzyl-amino]-N-isopropyl- benzamide 533-[Benzyl-(2-methyl-2H-pyrazole-3- 95 sulfonyl)-amino]-N-isopropyl-benzamide 54 3-[Benzyl-(4-methyl-3,4-dihydro-2H- 86benzo[1,4]oxazine-7-sulfonyl)-amino]- N-isopropyl-benzamide 553-[Benzyl-(3-oxo-3,4-dihydro-2H- 71benzo[1,4]oxazine-6-sulfonyl)-amino]- N-isopropyl-benzamide 562,3-Dihydro-benzo[1,4]dioxine-6- 79 sulfonic acidbenzyl-[3-(morpholine-4- carbonyl)-phenyl]-amide 574-Methyl-3,4-dihydro-2H- 46 benzo[1,4]oxazine-7-sulfonic acidbenzyl-[3-(morpholine-4-carbonyl)- phenyl]-amide 58Benzo[1,2,5]oxadiazole-4-sulfonic acid 41benzyl-[3-(morpholine-4-carbonyl)- phenyl]-amide 59Benzo[1,3]dioxole-5-sulfonic acid benzyl- 69[3-(morpholine-4-carbonyl)-phenyl]- amide 603-(Benzenesulfonyl-benzyl-amino)-N- 52 cyclopropyl-benzamide 613-(Benzenesulfonyl-benzyl-amino)-N- 77 cyclobutyl-benzamide 623-(Benzenesulfonyl-benzyl-amino)-N- 86 cyclopentyl-benzamide 633-(Benzenesulfonyl-benzyl-amino)-N- 93 (2-hydroxy-1,1-dimethyl-ethyl)-benzamide 64 3-(Benzenesulfonyl-benzyl-amino)-N- 54(2-hydroxy-1-methyl-ethyl)-benzamide 653-(Benzenesulfonyl-benzyl-amino)-N- 90(1-hydroxymethyl-propyl)-benzamide 663-(Benzenesulfonyl-benzyl-amino)-N- 88 (2-hydroxy-propyl)-benzamide 673-(Benzenesulfonyl-benzyl-amino)-N- 89 isobutyl-benzamide 683-(Benzenesulfonyl-benzyl-amino)-N- 80 ethyl-benzamide 693-(Benzenesulfonyl-benzyl-amino)-N- 82 (2-methoxy-ethyl)-benzamide 703-(Benzenesulfonyl-benzyl-amino)-N- 81 (2-hydroxy-ethyl)-benzamide 713-(Benzenesulfonyl-benzyl-amino)-N- 92 propyl-benzamide 723-(Benzenesulfonyl-benzyl-amino)-N- 78 (3-hydroxy-propyl)-benzamide 733-(Benzenesulfonyl-benzyl-amino)-N- 89 (4-hydroxy-butyl)-benzamide 743-(Benzenesulfonyl-benzyl-amino)-N- 89 cyclopropylmethyl-benzamide 753-(Benzenesulfonyl-benzyl-amino)-N- 69(2-hydroxy-1-hydroxymethyl-ethyl)- benzamide 763-(Benzenesulfonyl-benzyl-amino)-N- 85 ((R)-1-hydroxymethyl-propyl)-benzamide 77 5-[(Benzo[1,2,5]oxadiazole-4- 83sulfonyl)-benzyl-amino]-2-fluoro-N- isopropyl-benzamide 785-(Benzenesulfonyl-benzyl-amino)-2- 98 fluoro-N-isopropyl-benzamide 795-[Benzyl-(1-methyl-1H-imidazole-4- 58sulfonyl)-amino]-2-fluoro-N-isopropyl- benzamide 805-[Benzyl-(4-fluoro-benzenesulfonyl)- 92 amino]-2-fluoro-N-isopropyl-benzamide 81 5-[Benzyl-(2,3-dihydro- 92benzo[1,4]dioxine-6-sulfonyl)-amino]- 2-fluoro-N-isopropyl-benzamide 825-[Benzyl-(4-cyano-benzenesulfonyl)- 42 amino]-2-fluoro-N-isopropyl-benzamide 83 5-[Benzyl-(3-cyano-benzenesulfonyl)- 100amino]-2-fluoro-N-isopropyl- benzamide 845-[Benzyl-(2-cyano-benzenesulfonyl)- 80 amino]-2-fluoro-N-isopropyl-benzamide 85 5-[(Benzo[1,3]dioxole-5-sulfonyl)- 100benzyl-amino]-2-fluoro-N-isopropyl- benzamide 865-[Benzyl-(2,3-dihydro-benzofuran-5- 97sulfonyl)-amino]-2-fluoro-N-isopropyl- benzamide 875-[Benzyl-(pyridine-3-sulfonyl)- 91 amino]-2-fluoro-N-isopropyl-benzamide 88 5-[(4-Acetylamino-benzenesulfonyl)- 52benzyl-amino]-2-fluoro-N-isopropyl- benzamide 893-[(4-Chloro-benzyl)-(pyridine-3- 99 sulfonyl)-amino]-N-isopropyl-benzamide 90 3-[(4-Chloro-benzyl)-(3-oxo-3,4- 80dihydro-2H-benzo[1,4]oxazine-6- sulfonyl)-amino]-N-isopropyl- benzamide91 3-[(4-Chloro-benzyl)-(1-methyl-1H- 92 pyrazole-3-sulfonyl)-amino]-N-isopropyl-benzamide 92 3-[(4-Chloro-benzyl)-(1-methyl-1H- 79imidazole-4-sulfonyl)-amino]-N- isopropyl-benzamide 935-[Benzyl-(1-methyl-1H-pyrazole-3- 74sulfonyl)-amino]-2-fluoro-N-isopropyl- benzamide 943-[(4-Chloro-benzyl)-(4-methyl-3,4- 76 dihydro-2H-benzo[1,4]oxazine-6-sulfonyl)-amino]-N-isopropyl- benzamide 953-[(4-Chloro-benzyl)-(1,2-dimethyl- 941H-imidazole-4-sulfonyl)-amino]-N- isopropyl-benzamide 965-[Benzyl-(1,2-dimethyl-1H-imidazole- 61 4-sulfonyl)-amino]-2-fluoro-N-isopropyl-benzamide 97 5-[Benzyl-(2-methyl-2H-pyrazole-3- 48sulfonyl)-amino]-2-fluoro-N-isopropyl- benzamide 985-[(4-chloro-benzyl)-(pyridine-3- 96sulfonyl)-amino]-2-fluoro-N-isopropyl- benzamide 995-[(4-chloro-benzyl)-(1-methyl-1H- 98pyrazole-3-sulfonyl)-amino]-2-fluoro- N-isopropyl-benzamide 1005-[(4-chloro-benzyl)-(2-methyl-2H- 74pyrazole-3-sulfonyl)-amino]-2-fluoro- N-isopropyl-benzamide 1015-[(4-chloro-benzyl)-(1,2-dimethyl-1H- 94imidazole-4-sulfonyl)-amino]-2-fluoro- N-isopropyl-benzamide 1025-[(4-chloro-benzyl)-(1-methyl-1H- 75pyrazole-4-sulfonyl)-amino]-2-fluoro- N-isopropyl-benzamide 1035-[(4-Chloro-benzyl)-(3-cyano- 100 benzenesulfonyl)-amino]-2-fluoro-N-(2-hydroxy-ethyl)-benzamide 104 5-[(4-Chloro-benzyl)-(3-cyano- 101benzenesulfonyl)-amino]-2-fluoro-N- (1-hydroxymethyl-propyl)-benzamide105 N-(4-Chloro-benzyl)-3-cyano-N-[4- 82fluoro-3-(3-hydroxy-azetidine-1- carbonyl)-phenyl]-benzenesulfonamide106 5-[(4-Chloro-benzyl)-(3-cyano- 94benzenesulfonyl)-amino]-2-fluoro-N- (2-hydroxy-1-hydroxymethyl-ethyl)-benzamide 107 5-[(4-Chloro-benzyl)-(3-cyano- 98benzenesulfonyl)-amino]-2-fluoro-N- (2-hydroxy-1-methyl-ethyl)-benzamide108 5-[(4-Chloro-benzyl)-(3-cyano- 100benzenesulfonyl)-amino]-2-fluoro-N- (2-hydroxy-1,1-dimethyl-ethyl)-benzamide 109 5-[(4-Chloro-benzyl)-(3-cyano- 100benzenesulfonyl)-amino]-2-fluoro-N- (2-methoxy-ethyl)-benzamide 110N-(4-Chloro-benzyl)-3-cyano-N-[4- 89 fluoro-3-(3-hydroxy-piperidine-1-carbonyl)-phenyl]-benzenesulfonamide 111N-(4-Chloro-benzyl)-3-cyano-N-[4- 53fluoro-3-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-phenyl]-benzenesulfonamide 1123-[(4-Chloro-benzyl)-(pyridine-3-sulfonyl)- 91amino]-N-(2-hydroxy-ethyl)- benzamide 1133-[(4-Chloro-benzyl)-(pyridine-3- 95 sulfonyl)-amino]-N-(2-hydroxy-1-methyl-ethyl)-benzamide 114 3-[(4-Chloro-benzyl)-(pyridine-3- 77sulfonyl)-amino]-N-(1-hydroxymethyl- propyl)-benzamide 115Pyridine-3-sulfonic acid (4-chloro- 50benzyl)-[3-(3-hydroxy-azetidine-1- carbonyl)-phenyl]-amide 116Pyridine-3-sulfonic acid (4-chloro- 38benzyl)-[3-(3-hydroxy-piperidine-1- carbonyl)-phenyl]-amide 1173-[(4-Chloro-benzyl)-(pyridine-3- 95 sulfonyl)-amino]-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzamide 118 3-[(4-Chloro-benzyl)-(pyridine-3- 98sulfonyl)-amino]-N-(2-methoxy-ethyl)- benzamide 1193-[(4-Chloro-benzyl)-(pyridine-3- 99 sulfonyl)-amino]-N-cyclopropyl-benzamide 120 3-[(4-Chloro-benzyl)-(pyridine-3- 96sulfonyl)-amino]-N-cyclopentyl- benzamide 121 Pyridine-3-sulfonic acid(4-chloro- 45 benzyl)-[3-((R)-3-fluoro-pyrrolidine-1-carbonyl)-phenyl]-amide 122 3-[(4-Chloro-benzyl)-(pyridine-3- 100sulfonyl)-amino]-N-cyclobutyl- benzamide 123 Pyridine-3-sulfonic acid[3-(azetidine- 75 1-carbonyl)-phenyl]-(4-chloro-benzyl)- amide 1243-[(4-Chloro-benzyl)-(1-methyl-1H- 73 imidazole-4-sulfonyl)-amino]-N-methyl-benzamide 125 3-[(4-Chloro-benzyl)-(1-methyl-1H- 93imidazole-4-sulfonyl)-amino]-N-ethyl- benzamide 1263-[(4-Chloro-benzyl)-(1-methyl-1H- 66 imidazole-4-sulfonyl)-amino]-N-(2-methoxy-ethyl)-benzamide 127 3-[(4-Chloro-benzyl)-(1-methyl-1H- 95imidazole-4-sulfonyl)-amino]-N- cyclopropyl-benzamide 1283-[(4-Chloro-benzyl)-(1-methyl-1H- 93 imidazole-4-sulfonyl)-amino]-N-cyclopentyl-benzamide 129 3-[(4-Chloro-benzyl)-(1-methyl-1H- 96imidazole-4-sulfonyl)-amino]-N- cyclobutyl-benzamide 1301-Methyl-1H-imidazole-4-sulfonic acid 56[3-(azetidine-1-carbonyl)-phenyl]-(4- chloro-benzyl)-amide 1313-[(4-Chloro-benzyl)-(1-methyl-1H- 99pyrazole-3-sulfonyl)-amino]-N-methyl- benzamide 1323-[(4-Chloro-benzyl)-(1-methyl-1H- 100pyrazole-3-sulfonyl)-amino]-N-ethyl- benzamide 1333-[(4-Chloro-benzyl)-(1-methyl-1H- 98 pyrazole-3-sulfonyl)-amino]-N-(2-methoxy-ethyl)-benzamide 134 3-[(4-Chloro-benzyl)-(1-methyl-1H- 93pyrazole-3-sulfonyl)-amino]-N- cyclopropyl-benzamide 1353-[(4-Chloro-benzyl)-(1-methyl-1H- 99 pyrazole-3-sulfonyl)-amino]-N-cyclobutyl-benzamide 136 1-Methyl-1H-pyrazole-3-sulfonic acid 74[3-(azetidine-1-carbonyl)-phenyl]-(4- chloro-benzyl)-amide 1371-Methyl-1H-pyrazole-3-sulfonic acid 84 (4-chloro-benzyl)-[3-(3-methyl-piperidine-1-carbonyl)-phenyl]-amide 1383-[(4-Chloro-benzyl)-(1-methyl-1H- 100 pyrazole-3-sulfonyl)-amino]-N-cyclopentyl-benzamide 139 3-[(4-Chloro-benzyl)-(1-methyl-1H- 82pyrazole-3-sulfonyl)-amino]-N-(2- hydroxy-1-methyl-ethyl)-benzamide 1403-[(4-Chloro-benzyl)-(1-methyl-1H- 97 pyrazole-3-sulfonyl)-amino]-N-(1-hydroxymethyl-propyl)-benzamide 141 3-[(4-Chloro-benzyl)-(1-methyl-1H-100 pyrazole-3-sulfonyl)-amino]-N-(2- hydroxy-1,1-dimethyl-ethyl)-benzamide 139 3-[(4-chloro-benzyl)-(2-methyl-2H- 47pyrazole-3-sulfonyl)-amino]-N- cyclobutyl-benzamide 1403-[(4-chloro-benzyl)-(2-methyl-2H- 87 pyrazole-3-sulfonyl)-amino]-N-cyclopentyl-benzamide

Example 144 Kv1.5 Autopatch Electrophysiology Method

The external bathing solution contained (in mM): 150 NaCl, 10 KCl, 100Potassium Gluconate, 3 MgCl₂, 1 CaCl₂, 10 HEPES, pH 7.4. Patch pipetteswere filled with an electrode solution of composition (in mM): 160 KCl,0.5 MgCl₂, 10 HEPES, 1 EGTA, pH 7.4 with KOH.

Compounds were dissolved in DMSO (100%) and made-up in the externalbather at a concentration of 1 μM. All experiments were conducted atroom temperature (22-24° C.).

A cell suspension (10 ml), with a density of 100,000 cells/ml, wasaliquoted into a 15 ml centrifuge tube and transferred to an incubator(37° C., 5% CO₂) for approximately one hour before use. Following 60 minincubation, a tube was taken and centrifuged at 1000 rpm for 4 mins atroom temperature. 9.5 ml supernatant was thence discarded, leaving acell pellet at the bottom of the tube. The pellet was then suspendedusing 100 μl of cold (4° C.), filtered (0.22 μm), 0.2% BSA/bathersolution (0.02 g BSA/10 ml bather). The bottom of the tube was manuallyagitated gently until the solution became cloudy with cells. The 100 μlcell resuspension solution was then stored on the bench at 4° C. (usinga Peltier-based temperature control device) until used.

A length of capillary glass (1B150F-4, WPI) was dipped into the cellsuspension solution, such that ˜3 cm column of fluid was taken up bycapillary action. A Ag/AgCl wire was dropped into the non-dipped end ofthe capillary also. The outside of the solution-filled end of thecapillary was then dried and the capillary was loaded into theAutoPatch™.

Borosilicate glass patch pipettes (from 1.5 mm OD, thin-walledfilamented, GC150-TF capillary glass, Harvard) were pulled using a DMZpipette puller (Zeitz Instruments), and were back-filled using theinternal pipette solution, being careful that no bubbles remain at thetip or in the body of the pipette. Patch pipettes typically hadresistances of 2.3-3.5 MΩ. Once filled, the pipette tip and a proportionof the shaft (˜15 mm) were dipped into Sigmacote (Sigma). The recordingpipette was then loaded into the AutoPatch™. Automated patch-clampingwas initiated by the operator, but thereafter AutoPatch.exe continuedthe experiment providing that pre-set conditions and criteria weresatisfied.

Whole cell patch-clamp recordings were made using the AutoPatch™ rig,which incorporated an EPC9 amplifier (HEKA, Germany) under control ofPulse software (v8.54, HEKA, Germany), a motion controller with 2translators (Newport, UK), valve controller (VF1) and a c-level suctiondevice all at room temperature (22-24° C.). This equipment wascompletely under the control of AutoPatch.exe and operator interventionwas only made when there was a requirement to refill the drug reservoirsor to prevent the loss of a cell due to a technical error. Cells with anR_(series) greater than 18 MΩ were discounted from the experiment.

Qualification stages prior to perfusion and drug application ensuredthat the observed current met the criteria for the experiment. Onlythose cells with an I_(K)>500 pA were used for experiments. Cells werecontinuously perfused with external solution at a flow rate of 1.8-2ml/minute. The perfusion chamber had a working volume of 80-85 μl andallowed for rapid exchange of drug solutions. Online analysis of thehKv1.5 current during the application of compounds was performed by theAutoPatch™ software. Voltage-step protocols and analysis of data wasperformed as described for conventional electrophysiology.

Electrophysiology voltage-step protocols and analysis of data wasperformed as follows. Data was sampled at 5 kHz, and filtered with a −3dB bandwidth of 2.5 kHz. Cells were held at a voltage of −80 mV.Currents were evoked to a voltage step for 1000 ms in duration at 0 mVevery 5 s. Currents were analysed using Pulsefit software (v8.54, HEKA,Germany), with the total charge measured during the whole of the voltagestep. All other plots were produced using Igor Pro (WaveMetries)

Example 145 Summary of Kv1.5 Biological Activity

hKv1.5 Example Name % inh. 1 3-[(4-Chloro-benzyl)-(1-methyl-1H- 48pyrazole-3-sulfonyl)-amino]-N-(2- hydroxy-ethyl)-benzamide 2N-Benzyl-3-[benzyl-(1-methyl-1H- 16 imidazole-4-sulfonyl)-amino]-benzamide 3 3-[Benzyl-(pyridine-3-sulfonyl)- 52amino]-N-isopropyl-benzamide 4 3-(Benzenesulfonyl-benzyl-amino)-N- 99(1H-indazol-6-yl)-benzamide 5 3-[(4-Acetylamino-benzenesulfonyl)- 18benzyl-amino]-N-isopropyl-benzamide 6 5-[Benzyl-(3-oxo-3,4-dihydro-2H-46 benzo[1,4]oxazine-6-sulfonyl)-amino]- 2-fluoro-N-isopropyl-benzamide7 3-[(4-Chloro-benzyl)-(2-methyl-2H- 54 pyrazole-3-sulfonyl)-amino]-N-isopropyl-benzamide 10 3-(Benzenesulfonyl-benzyl-amino)-N- 83benzyl-benzamide 11 3-(Benzenesulfonyl-benzyl-amino)-N- 61isopropyl-benzamide 12 3-(Benzenesulfonyl-benzyl-amino)-N- 98phenethyl-benzamide 13 N-Benzyl-N-[3-(4-phenyl-piperidine-1- 94carbonyl)-phenyl]-benzenesulfonamide 14N-Benzyl-N-[3-(3-phenyl-piperidine-1- 81carbonyl)-phenyl]-benzenesulfonamide 15N-Benzyl-N-[3-(2-phenyl-morpholine- 64 4-carbonyl)-phenyl]-benzenesulfonamide 16 N-Benzyl-N-[3-(4-phenoxy-piperidine- 861-carbonyl)-phenyl]- benzenesulfonamide 173-(Benzenesulfonyl-benzyl-amino)-N- 92 (3-phenyl-propyl)-benzamide 183-(Benzenesulfonyl-benzyl-amino)-N- 20 methyl-benzamide 193-(benzenesulfonyl-benzyl-amino)-N- 67 tert-butyl-benzamide 20N-benzyl-N-[3-(3-phenyl-piperidine-1- 46carbonyl)-phenyl]-methanesulfonamide 21N-benzyl-N-[3-(2-phenyl-morpholine- 16 4-carbonyl)-phenyl]-methanesulfonamide 22 N-benzyl-N-[3-(4-phenoxy-piperidine- 151-carbonyl)-phenyl]- methanesulfonamide 23N-benzyl-N-[3-(4-phenyl-piperidine-1- 13carbonyl)-phenyl]-methanesulfonamide 24 1-Methyl-1H-imidazole-4-sulfonicacid 13 benzyl-[3-(4-phenyl-piperidine-1- carbonyl)-phenyl]-amide 25N-Benzyl-N-[3-(morpholine-4- 19 carbonyl)-phenyl]-benzenesulfonamide 263-(benzenesulfonyl-benzyl-amino)-N- 88 pyridin-2-ylmethyl-benzamide 273-(benzenesulfonyl-benzyl-amino)-N- 81 (1H-indazol-5-yl)-benzamide 283-(benzenesulfonyl-benzyl-amino)-N- 98(4-imidazol-1-yl-phenyl)-benzamide 293-(benzenesulfonyl-benzyl-amino)-N- 98 (4-pyrazol-1-yl-phenyl)-benzamide30 3-(benzenesulfonyl-benzyl-amino)-N- 86[1,3,4]thiadiazol-2-yl-benzamide 31 3-(benzenesulfonyl-benzyl-amino)-N-95 thiazol-2-yl-benzamide 32 N-[4-(aminocarbonyl)phenyl]-3- 86[benzyl(phenylsulfonyl)amino]benzamide 33 N-[3-(aminocarbonyl)phenyl]-3-85 [benzyl(phenylsulfonyl)amino]benzamide 343-(benzenesulfonyl-benzyl-amino)-N- 84 phenyl-benzamide 351-Methyl-1H-imidazole-4-sulfonic acid 16benzyl-[3-(2-phenyl-morpholine-4- carbonyl)-phenyl]-amide 363-[Benzyl-(1,2-dimethyl-1H-imidazole- 20 4-sulfonyl)-amino]-N-isopropyl-benzamide 37 3-[Benzyl-(1-methyl-1H-pyrazole-3- 21sulfonyl)-amino]-N-isopropyl- benzamide 383-[Benzyl-(2,4-dimethyl-thiazole-5- 10 sulfonyl)-amino]-N-isopropyl-benzamide 39 N-benzyl-2-fluoro-N-[3-(morpholine-4- 12carbonyl)-phenyl]-benzenesulfonamide 403-[benzyl-(2-fluoro-benzenesulfonyl)- 16 amino]-N,N-dimethyl-benzamide41 3-[benzyl-(3-fluoro-benzenesulfonyl)- 7 amino]-N,N-dimethyl-benzamide42 N-benzyl-4-fluoro-N-[3-(morpholine-4- 30carbonyl)-phenyl]-benzenesulfonamide 433-[benzyl-(4-fluoro-benzenesulfonyl)- 31 amino]-N,N-dimethyl-benzamide44 3-[benzyl-(4-fluoro-benzenesulfonyl)- 65 amino]-N-isopropyl-benzamide45 1-Methyl-1H-imidazole-4-sulfonic acid 30benzyl-{3-[4-(2-fluoro-phenyl)- piperazine-1-carbonyl]-phenyl}-amide 463-[benzyl-(2-fluoro-benzenesulfonyl)- 12 amino]-N-isopropyl-benzamide 473-[benzyl-(3-fluoro-benzenesulfonyl)- 44 amino]-N-isopropyl-benzamide 481-Methyl-1H-imidazole-4-sulfonic acid 10 benzyl-[3-(4-cyclohexylmethyl-piperazine-1-carbonyl)-phenyl]-amide 493-[Benzyl-(2,3-dihydro-benzofuran-5- 98 sulfonyl)-amino]-N-isopropyl-benzamide 50 3-[Benzyl-(2,2-dimethyl-chroman-6- 85sulfonyl)-amino]-N-isopropyl- benzamide 51 3-[Benzyl-(2,3-dihydro- 98benzo[1,4]dioxine-6-sulfonyl)-amino]- N-isopropyl-benzamide 523-[(1-Acetyl-2,3-dihydro-1H-indole-5- 38sulfonyl)-benzyl-amino]-N-isopropyl- benzamide 533-[Benzyl-(2-methyl-2H-pyrazole-3- 83 sulfonyl)-amino]-N-isopropyl-benzamide 54 3-[Benzyl-(4-methyl-3,4-dihydro-2H- 80benzo[1,4]oxazine-7-sulfonyl)-amino]- N-isopropyl-benzamide 553-[Benzyl-(3-oxo-3,4-dihydro-2H- 48benzo[1,4]oxazine-6-sulfonyl)-amino]- N-isopropyl-benzamide 562,3-Dihydro-benzo[1,4]dioxine-6- 37 sulfonic acidbenzyl-[3-(morpholine-4- carbonyl)-phenyl]-amide 574-Methyl-3,4-dihydro-2H- 18 benzo[1,4]oxazine-7-sulfonic acidbenzyl-[3-(morpholine-4-carbonyl)- phenyl]-amide 58Benzo[1,2,5]oxadiazole-4-sulfonic acid 25benzyl-[3-(morpholine-4-carbonyl)- phenyl]-amide 59Benzo[1,3]dioxole-5-sulfonic acid benzyl- 41[3-(morpholine-4-carbonyl)-phenyl]- amide 603-(Benzenesulfonyl-benzyl-amino)-N- 54 cyclopropyl-benzamide 613-(Benzenesulfonyl-benzyl-amino)-N- 82 cyclobutyl-benzamide 623-(Benzenesulfonyl-benzyl-amino)-N- 92 cyclopentyl-benzamide 633-(Benzenesulfonyl-benzyl-amino)-N- 86 (2-hydroxy-1,1-dimethyl-ethyl)-benzamide 64 3-(Benzenesulfonyl-benzyl-amino)-N- 83(2-hydroxy-1-methyl-ethyl)-benzamide 653-(Benzenesulfonyl-benzyl-amino)-N- 47(1-hydroxymethyl-propyl)-benzamide 663-(Benzenesulfonyl-benzyl-amino)-N- 47 (2-hydroxy-propyl)-benzamide 673-(Benzenesulfonyl-benzyl-amino)-N- 78 isobutyl-benzamide 683-(Benzenesulfonyl-benzyl-amino)-N- 43 ethyl-benzamide 693-(Benzenesulfonyl-benzyl-amino)-N- 43 (2-methoxy-ethyl)-benzamide 703-(Benzenesulfonyl-benzyl-amino)-N- 38 (2-hydroxy-ethyl)-benzamide 713-(Benzenesulfonyl-benzyl-amino)-N- 75 propyl-benzamide 723-(Benzenesulfonyl-benzyl-amino)-N- 57 (3-hydroxy-propyl)-benzamide 733-(Benzenesulfonyl-benzyl-amino)-N- 45 (4-hydroxy-butyl)-benzamide 743-(Benzenesulfonyl-benzyl-amino)-N- 79 cyclopropylmethyl-benzamide 753-(Benzenesulfonyl-benzyl-amino)-N- 37(2-hydroxy-1-hydroxymethyl-ethyl)- benzamide 763-(Benzenesulfonyl-benzyl-amino)-N- 72 ((R)-1-hydroxymethyl-propyl)-benzamide 77 5-[(Benzo[1,2,5]oxadiazole-4- 73sulfonyl)-benzyl-amino]-2-fluoro-N- isopropyl-benzamide 785-(Benzenesulfonyl-benzyl-amino)-2- 74 fluoro-N-isopropyl-benzamide 795-[Benzyl-(1-methyl-1H-imidazole-4- 13sulfonyl)-amino]-2-fluoro-N-isopropyl- benzamide 805-[Benzyl-(4-fluoro-benzenesulfonyl)- 94 amino]-2-fluoro-N-isopropyl-benzamide 81 5-[Benzyl-(2,3-dihydro- 78benzo[1,4]dioxine-6-sulfonyl)-amino]- 2-fluoro-N-isopropyl-benzamide 825-[Benzyl-(4-cyano-benzenesulfonyl)- 46 amino]-2-fluoro-N-isopropyl-benzamide 83 5-[Benzyl-(3-cyano-benzenesulfonyl)- 96amino]-2-fluoro-N-isopropyl- benzamide 845-[Benzyl-(2-cyano-benzenesulfonyl)- 58 amino]-2-fluoro-N-isopropyl-benzamide 85 5-[(Benzo[1,3]dioxole-5-sulfonyl)- 89benzyl-amino]-2-fluoro-N-isopropyl- benzamide 865-[Benzyl-(2,3-dihydro-benzofuran-5- 78sulfonyl)-amino]-2-fluoro-N-isopropyl- benzamide 875-[Benzyl-(pyridine-3-sulfonyl)- 75 amino]-2-fluoro-N-isopropyl-benzamide 88 5-[(4-Acetylamino-benzenesulfonyl)- 45benzyl-amino]-2-fluoro-N-isopropyl- benzamide 893-[(4-Chloro-benzyl)-(pyridine-3- 87 sulfonyl)-amino]-N-isopropyl-benzamide 90 3-[(4-Chloro-benzyl)-(3-oxo-3,4- 69dihydro-2H-benzo[1,4]oxazine-6- sulfonyl)-amino]-N-isopropyl- benzamide91 3-[(4-Chloro-benzyl)-(1-methyl-1H- 92 pyrazole-3-sulfonyl)-amino]-N-isopropyl-benzamide 92 3-[(4-Chloro-benzyl)-(1-methyl-1H- 40imidazole-4-sulfonyl)-amino]-N- isopropyl-benzamide 935-[Benzyl-(1-methyl-1H-pyrazole-3- 28sulfonyl)-amino]-2-fluoro-N-isopropyl- benzamide 943-[(4-Chloro-benzyl)-(4-methyl-3,4- 82 dihydro-2H-benzo[1,4]oxazine-6-sulfonyl)-amino]-N-isopropyl- benzamide 953-[(4-Chloro-benzyl)-(1,2-dimethyl- 831H-imidazole-4-sulfonyl)-amino]-N- isopropyl-benzamide 965-[Benzyl-(1,2-dimethyl-1H-imidazole- 21 4-sulfonyl)-amino]-2-fluoro-N-isopropyl-benzamide 97 5-[Benzyl-(2-methyl-2H-pyrazole-3- 17sulfonyl)-amino]-2-fluoro-N-isopropyl- benzamide 985-[(4-chloro-benzyl)-(pyridine-3- 84sulfonyl)-amino]-2-fluoro-N-isopropyl- benzamide 995-[(4-chloro-benzyl)-(1-methyl-1H- 87pyrazole-3-sulfonyl)-amino]-2-fluoro- N-isopropyl-benzamide 1005-[(4-chloro-benzyl)-(2-methyl-2H- 46pyrazole-3-sulfonyl)-amino]-2-fluoro- N-isopropyl-benzamide 1015-[(4-chloro-benzyl)-(1,2-dimethyl-1H- 38imidazole-4-sulfonyl)-amino]-2-fluoro- N-isopropyl-benzamide 1025-[(4-chloro-benzyl)-(1-methyl-1H- 55pyrazole-4-sulfonyl)-amino]-2-fluoro- N-isopropyl-benzamide 1035-[(4-Chloro-benzyl)-(3-cyano- 99 benzenesulfonyl)-amino]-2-fluoro-N-(2-hydroxy-ethyl)-benzamide 104 5-[(4-Chloro-benzyl)-(3-cyano- 98benzenesulfonyl)-amino]-2-fluoro-N- (1-hydroxymethyl-propyl)-benzamide105 N-(4-Chloro-benzyl)-3-cyano-N-[4- 50fluoro-3-(3-hydroxy-azetidine-1- carbonyl)-phenyl]-benzenesulfonamide106 5-[(4-Chloro-benzyl)-(3-cyano- 77benzenesulfonyl)-amino]-2-fluoro-N- (2-hydroxy-1-hydroxymethyl-ethyl)-benzamide 107 5-[(4-Chloro-benzyl)-(3-cyano- 99benzenesulfonyl)-amino]-2-fluoro-N- (2-hydroxy-1-methyl-ethyl)-benzamide108 5-[(4-Chloro-benzyl)-(3-cyano- 99benzenesulfonyl)-amino]-2-fluoro-N- (2-hydroxy-1,1-dimethyl-ethyl)-benzamide 109 5-[(4-Chloro-benzyl)-(3-cyano- 99benzenesulfonyl)-amino]-2-fluoro-N- (2-methoxy-ethyl)-benzamide 110N-(4-Chloro-benzyl)-3-cyano-N-[4- 85 fluoro-3-(3-hydroxy-piperidine-1-carbonyl)-phenyl]-benzenesulfonamide 111N-(4-Chloro-benzyl)-3-cyano-N-[4- 41fluoro-3-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-phenyl]-benzenesulfonamide 1123-[(4-Chloro-benzyl)-(pyridine-3-sulfonyl)- 65amino]-N-(2-hydroxy-ethyl)- benzamide 1133-[(4-Chloro-benzyl)-(pyridine-3- 70 sulfonyl)-amino]-N-(2-hydroxy-1-methyl-ethyl)-benzamide 114 3-[(4-Chloro-benzyl)-(pyridine-3- 45sulfonyl)-amino]-N-(1-hydroxymethyl- propyl)-benzamide 115Pyridine-3-sulfonic acid (4-chloro- 10benzyl)-[3-(3-hydroxy-azetidine-1- carbonyl)-phenyl]-amide 116Pyridine-3-sulfonic acid (4-chloro- 13benzyl)-[3-(3-hydroxy-piperidine-1- carbonyl)-phenyl]-amide 1173-[(4-Chloro-benzyl)-(pyridine-3- 91 sulfonyl)-amino]-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzamide 118 3-[(4-Chloro-benzyl)-(pyridine-3- 88sulfonyl)-amino]-N-(2-methoxy-ethyl)- benzamide 1193-[(4-Chloro-benzyl)-(pyridine-3- 98 sulfonyl)-amino]-N-cyclopropyl-benzamide 120 3-[(4-Chloro-benzyl)-(pyridine-3- 84sulfonyl)-amino]-N-cyclopentyl- benzamide 121 Pyridine-3-sulfonic acid(4-chloro- 20 benzyl)-[3-((R)-3-fluoro-pyrrolidine-1-carbonyl)-phenyl]-amide 122 3-[(4-Chloro-benzyl)-(pyridine-3- 97sulfonyl)-amino]-N-cyclobutyl- benzamide 123 Pyridine-3-sulfonic acid[3-(azetidine- 52 1-carbonyl)-phenyl]-(4-chloro-benzyl)- amide 1243-[(4-Chloro-benzyl)-(1-methyl-1H- 10 imidazole-4-sulfonyl)-amino]-N-methyl-benzamide 125 3-[(4-Chloro-benzyl)-(1-methyl-1H- 54imidazole-4-sulfonyl)-amino]-N-ethyl- benzamide 1263-[(4-Chloro-benzyl)-(1-methyl-1H- 21 imidazole-4-sulfonyl)-amino]-N-(2-methoxy-ethyl)-benzamide 127 3-[(4-Chloro-benzyl)-(1-methyl-1H- 49imidazole-4-sulfonyl)-amino]-N- cyclopropyl-benzamide 1283-[(4-Chloro-benzyl)-(1-methyl-1H- 69 imidazole-4-sulfonyl)-amino]-N-cyclopentyl-benzamide 129 3-[(4-Chloro-benzyl)-(1-methyl-1H- 57imidazole-4-sulfonyl)-amino]-N- cyclobutyl-benzamide 1301-Methyl-1H-imidazole-4-sulfonic acid 25[3-(azetidine-1-carbonyl)-phenyl]-(4- chloro-benzyl)-amide 1313-[(4-Chloro-benzyl)-(1-methyl-1H- 78pyrazole-3-sulfonyl)-amino]-N-methyl- benzamide 1323-[(4-Chloro-benzyl)-(1-methyl-1H- 99pyrazole-3-sulfonyl)-amino]-N-ethyl- benzamide 1333-[(4-Chloro-benzyl)-(1-methyl-1H- 84 pyrazole-3-sulfonyl)-amino]-N-(2-methoxy-ethyl)-benzamide 134 3-[(4-Chloro-benzyl)-(1-methyl-1H- 97pyrazole-3-sulfonyl)-amino]-N- cyclopropyl-benzamide 1353-[(4-Chloro-benzyl)-(1-methyl-1H- 99 pyrazole-3-sulfonyl)-amino]-N-cyclobutyl-benzamide 136 1-Methyl-1H-pyrazole-3-sulfonic acid 64[3-(azetidine-1-carbonyl)-phenyl]-(4- chloro-benzyl)-amide 1371-Methyl-1H-pyrazole-3-sulfonic acid 69 (4-chloro-benzyl)-[3-(3-methyl-piperidine-1-carbonyl)-phenyl]-amide 1383-[(4-Chloro-benzyl)-(1-methyl-1H- 100 pyrazole-3-sulfonyl)-amino]-N-cyclopentyl-benzamide 139 3-[(4-Chloro-benzyl)-(1-methyl-1H- 50pyrazole-3-sulfonyl)-amino]-N-(2- hydroxy-1-methyl-ethyl)-benzamide 1403-[(4-Chloro-benzyl)-(1-methyl-1H- 70 pyrazole-3-sulfonyl)-amino]-N-(1-hydroxymethyl-propyl)-benzamide 141 3-[(4-Chloro-benzyl)-(1-methyl-1H-78 pyrazole-3-sulfonyl)-amino]-N-(2- hydroxy-1,1-dimethyl-ethyl)-benzamide 139 3-[(4-chloro-benzyl)-(2-methyl-2H- 59pyrazole-3-sulfonyl)-amino]-N- cyclobutyl-benzamide 1403-[(4-chloro-benzyl)-(2-methyl-2H- 55 pyrazole-3-sulfonyl)-amino]-N-cyclopentyl-benzamide

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The invention claimed is:
 1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: X₁ is selectedfrom the group consisting of CH₂, C(═O), C(═NH), and NHC(═O); R₁ isselected from the group consisting of optionally substituted arylalkyl,wherein the aryl substituents are cyano, halogen, hydroxyl, nitro,trifluoromethyl, alkyl, alkylthio, alkoxy, amino, alkylamino,dialkylamino, alkanoyl, amido, N-alkylamido, N,N-dialkylamino,sulfonamido, aryl, or heteroaryl, and optionally substitutedheteroarylalkyl, wherein the heteroaryl substituents are alkyl,cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic,heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl,carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulphamoyl,sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or when positionedadjacent to each other, may combine to form cycloalkyl orheteroalicyclic ring systems; R₂ is selected from the group consistingof optionally substituted alkyl, wherein the alkyl substituents arecyano, halogen, hydroxyl, alkylamino, dialkylamino, amido, alkylamido,dialkylamido, alkanoyl, alkoxy, sulfonamido, nitro, aryl, or heteroaryl,optionally substituted aryl, wherein the aryl substituents are cyano,halogen, hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy,amino, alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, optionallysubstituted heteroaryl, wherein the heteroaryl substituents are alkyl,cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic,heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl,carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulphamoyl,sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or when positionedadjacent to each other, may combine to form cycloalkyl orheteroalicyclic ring systems, and NR₂₄R₂₅; R₃ is selected from the groupconsisting of hydrogen, halogen, hydroxy, alkoxy, aryloxy, optionallysubstituted alkyl, wherein the alkyl substituents are cyano, halogen,hydroxyl, alkylamino, dialkylamino, amido, alkylamido, dialkylamido,alkanoyl, alkoxy, sulfonamido, nitro, aryl, or heteroaryl, amino, aminosulfonyl, and cyano; R₄ and R₅ together with the N to which they areattached form a saturated or partially saturated 4-7 membered ring withthe general formula (II):

wherein: X₂ is C(═O), CH₂ or CH(R₆) or C(R₆)(R₆); wherein each R₆independently is amino, amino carbonyl, hydroxy, acyl, optionallysubstituted alkoxy, wherein the alkyl substituents are cyano, halogen,hydroxyl, alkylamino, dialkylamino, amido, alkylamido, dialkylamido,alkanoyl, alkoxy, sulfonamido, nitro, aryl, or heteroaryl, optionallysubstituted aryloxy, wherein the aryl substituents are cyano, halogen,hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, amino,alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, optionallysubstituted alkyl, wherein the alkyl substituents are cyano, halogen,hydroxyl, alkylamino, dialkylamino, amido, alkylamido, dialkylamido,alkanoyl, alkoxy, sulfonamido, nitro, aryl, or heteroaryl, optionallysubstituted cycloalkyl, wherein the cycloalkyl substituents are alkyl,cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic,heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl,carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulphamoyl,sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or one or more ringcarbons may be bonded via a double bond to a group selected from NH, Sand O, optionally substituted arylalkyl, wherein the aryl substituentsare cyano, halogen, hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio,alkoxy, amino, alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, optionallysubstituted aryl wherein the aryl substituents are cyano, halogen,hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, amino,alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido, sulfonamido,aryl, or heteroaryl, or optionally substituted heteroaryl, wherein theheteroaryl substituents are alkyl, cycloalkyl, —O—C(halogen)₃, biaryl,carbocyclic aryl, heteroalicyclic, heteroaryl, acyl, amidino, amido,amino, alkyoxyamino, carbamoyl, carboxy, cyano, ether, hydroxyl, imino,halo, nitro, sulphamoyl, sulfonyl, sulphinyl, sulphenyl, sulfonamido orurea, or when positioned adjacent to each other, may combine to formcycloalkyl or heteroalicyclic ring systems; X₃ is CH₂, CH(R₇),C(R₇)(R₇), NH, N(R₈), O or S; wherein each R₇ independently is amino,amino carbonyl, hydroxy, acyl, optionally substituted alkoxy, whereinthe alkyl substituents are cyano, halogen, hydroxyl, alkylamino,dialkylamino, amido, alkylamido, dialkylamido, alkanoyl, alkoxy,sulfonamido, nitro, aryl, or heteroaryl, optionally substituted aryloxy,wherein the aryl substituents are cyano, halogen, hydroxyl, nitro,trifluoromethyl, alkyl, alkylthio, alkoxy, amino, alkylamino,dialkylamino, alkanoyl, amido, N-alkylamido, N,N-dialkylamino,sulfonamido, aryl, or heteroaryl, optionally substituted alkyl, whereinthe alkyl substituents are cyano, halogen, hydroxyl, alkylamino,dialkylamino, amido, alkylamido, dialkylamido, alkanoyl, alkoxy,sulfonamido, nitro, aryl, or heteroaryl, optionally substitutedcycloalkyl, wherein the cycloalkyl substituents are alkyl, cycloalkyl,—O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic, heteroaryl,acyl, amidino, amido, amino, alkyoxyamino, carbamoyl, carboxy, cyano,ether, hydroxyl, imino, halo, nitro, sulphamoyl, sulfonyl, sulphinyl,sulphenyl, sulfonamido or urea, or one or more ring carbons may bebonded via a double bond to a group selected from NH, S and O,optionally substituted arylalkyl, wherein the aryl substituents arecyano, halogen, hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio,alkoxy, amino, alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, optionallysubstituted aryl wherein the aryl substituents are cyano, halogen,hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, amino,alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,NN-dialkylamino, sulfonamido, aryl, or heteroaryl, or optionallysubstituted heteroaryl, wherein the heteroaryl substituents are alkyl,cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic,heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl,carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulphamoyl,sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or when positionedadjacent to each other, may combine to form cycloalkyl orheteroalicyclic ring systems; R₈ is acyl, optionally substituted alkyl,wherein the alkyl substituents are cyano, halogen, hydroxyl, alkylamino,dialkylamino, amido, alkylamido, dialkylamido, alkanoyl, alkoxy,sulfonamido, nitro, aryl, or heteroaryl, optionally substitutedcycloalkyl, wherein the cycloalkyl substituents are alkyl, cycloalkyl,—O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic, heteroaryl,acyl, amidino, amido, amino, alkyoxyamino, carbamoyl, carboxy, cyano,ether, hydroxyl, imino, halo, nitro, sulphamoyl, sulfonyl, sulphinyl,sulphenyl, sulfonamido or urea, or one or more ring carbons may bebonded via a double bond to a group selected from NH, S and O,optionally substituted arylalkyl, wherein the aryl substituents arecyano, halogen, hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio,alkoxy, amino, alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, optionallysubstituted aryl, wherein aryl the substituents are cyano, halogen,hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, amino,alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, or optionallysubstituted heteroaryl, wherein aryl the substituents are cyano,halogen, hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy,amino, alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,NN-dialkylamino, sulfonamido, aryl, or heteroaryl; R₂₄ and R₂₅ are thesame or different and each is hydrogen, optionally substituted alkyl,wherein the alkyl substituents are cyano, halogen, hydroxyl, alkylamino,dialkylamino, amido, alkylamido, dialkylamido, alkanoyl, alkoxy,sulfonamido, nitro, aryl, or heteroaryl, optionally substitutedcycloalkyl, wherein the cycloalkyl substituents are alkyl, cycloalkyl,—O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic, heteroaryl,acyl, amidino, amido, amino, alkyoxyamino, carbamoyl, carboxy, cyano,ether, hydroxyl, imino, halo, nitro, sulphamoyl, sulfonyl, sulphinyl,sulphenyl, sulfonamido or urea, or one or more ring carbons may bebonded via a double bond to a group selected from NH, S and O,optionally substituted arylalkyl, wherein the cycloalkyl substituentsare alkyl, cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl,heteroalicyclic, heteroaryl, acyl, amidino, amido, amino, alkyoxyamino,carbamoyl, carboxy, cyano, ether, hydroxyl, imino, halo, nitro,sulphamoyl, sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or oneor more ring carbons may be bonded via a double bond to a group selectedfrom NH, S and O, optionally substituted aryl, wherein the arylsubstituents are cyano, halogen, hydroxyl, nitro, trifluoromethyl,alkyl, alkylthio, alkoxy, amino, alkylamino, dialkylamino, alkanoyl,amido, N-alkylamido, N,N-dialkylamino, sulfonamido, aryl, or heteroaryl,or optionally substituted heteroaryl, wherein the heteroarylsubstituents are alkyl, cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclicaryl, heteroalicyclic, heteroaryl, acyl, amidino, amido, amino,alkyoxyamino, carbamoyl, carboxy, cyano, ether, hydroxyl, imino, halo,nitro, sulphamoyl, sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea,or when positioned adjacent to each other, may combine to formcycloalkyl or heteroalicyclic ring systems; n=1 or 2; and m=1, 2 or 3.2. A compound according to claim 1, wherein X₁ is C(═O), or apharmaceutically acceptable salt thereof.
 3. A compound according claim2, wherein R₂ is NR₂₄R₂₅, or a pharmaceutically acceptable salt thereof.4. A compound according to claim 3, wherein R₂₄ and R₂₅ are the same ordifferent and each represents hydrogen or optionally substitutedC₁₋₃alkyl), or a pharmaceutically acceptable salt thereof.
 5. A compoundof formula (I):

or a pharmaceutically acceptable salt thereof, wherein: X₁ is C(═O); R₁is selected from the group consisting of optionally substitutedarylalkyl, wherein the aryl substituents are cyano, halogen, hydroxyl,nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, amino, alkylamino,dialkylamino, alkanoyl, amido, N-alkylamido, sulfonamido, aryl, orheteroaryl, and optionally substituted heteroarylalkyl, wherein theheteroaryl substituents are alkyl, cycloalkyl, —O—C(halogen)₃, biaryl,carbocyclic aryl, heteroalicyclic, heteroaryl, acyl, amidino, amido,amino, alkyoxyamino, carbamoyl, carboxy, cyano, ether, hydroxyl, imino,halo, nitro, sulphamoyl, sulfonyl, sulphinyl, sulphenyl, sulfonamido orurea, or when positioned adjacent to each other, may combine to formcycloalkyl or heteroalicyclic ring systems; R₂ is formula (III), (IV) or(V):

wherein: A, D, E, G, and J are the same or different and each is C or Nwith the provisos that in each instance: 1) at least one of A, D, E, G,or J is N; 2) when R₂ is formula (III), E may also be O or S; and 3)when R₂ is formula (IV), A may also be O or S; R₉ and R₁₀ are the sameor different and each is hydrogen, halogen, hydroxy, cyano, optionallyamino, acyl, optionally substituted C₁₋₃ alkyl, wherein the C₁₋₃ alkylsubstituents are cyano, halogen, hydroxyl, alkylamino, dialkylamino,amido, alkylamido, dialkylamido, alkanoyl, alkoxy, sulfonamido, nitro,aryl, or heteroaryl, optionally substituted arylalkyl, wherein the arylsubstituents are cyano, halogen, hydroxyl, nitro, trifluoromethyl,alkyl, alkylthio, alkoxy, amino, alkylamino, dialkylamino, alkanoyl,amido, N-alkylamido, N,N-dialkylamino, sulfonamido, aryl, or heteroaryl,optionally substituted aryl, wherein the aryl substituents are cyano,halogen, hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy,amino, alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,NN-dialkylamino, sulfonamido, aryl, or heteroaryl, or optionallysubstituted heteroaryl, wherein the heteroaryl substituents are alkyl,cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic,heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl,carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulphamoyl,sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea or when positionedadjacent to each other, may combine to form cycloalkyl orheteroalicyclic ring systems, or may be taken together to form anoptionally substituted saturated or partially saturated 5-7 memberedheterocyclic or carbocyclic ring, wherein the heterocyclic orcarbocyclic ring substituents are alkyl, cycloalkyl, —O—C(halogen)₃,biaryl, carbocyclic aryl, heteroalicyclic, heteroaryl, acyl, amidino,amido, amino, alkyoxyamino, carbamoyl, carboxy, cyano, ether, hydroxyl,imino, halo, nitro, sulphamoyl, sulfonyl, sulphinyl, sulphenyl,sulfonamido or urea; R₃ is selected from the group consisting ofhydrogen, halogen, hydroxy, alkoxy, aryloxy, optionally substitutedalkyl, wherein the alkyl substituents are cyano, halogen, hydroxyl,nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, amino, alkylamino,dialkylamino, alkanoyl, amido, N-alkylamido, N,N-dialkylamino,sulfonamido, aryl, or heteroaryl, amino, amino sulfonyl, and cyano; R₄and R₅ together with the N to which they are attached form a saturatedor partially saturated 4-7 membered ring with the general formula (II):

wherein: X₂ is C(═O), CH₂, CH(R₆), or C(R₆)(R₆); wherein each R₆independently is amino, amino carbonyl, hydroxy, acyl, optionallysubstituted alkoxy, wherein the alkyl substituents are cyano, halogen,hydroxyl, alkylamino, dialkylamino, amido, alkylamido, dialkylamido,alkanoyl, alkoxy, sulfonamido, nitro, aryl, or heteroaryl, optionallysubstituted aryloxy, wherein the aryl substituents are cyano, halogen,hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, amino,alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, optionallysubstituted alkyl, wherein the alkyl substituents are cyano, halogen,hydroxyl, alkylamino, dialkylamino, amido, alkylamido, dialkylamido,alkanoyl, alkoxy, sulfonamido, nitro, aryl, or heteroaryl, optionallysubstituted cycloalkyl, wherein the cycloalkyl substituents are alkyl,cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic,heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl,carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulphamoyl,sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or one or more ringcarbons may be bonded via a double bond to a group selected from NH, Sand O, optionally substituted arylalkyl, wherein the aryl substituentsare cyano, halogen, hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio,alkoxy, amino, alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, optionallysubstituted aryl, wherein the aryl substituents are cyano, halogen,hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, amino,alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,NN-dialkylamino, sulfonamido, aryl, or heteroaryl, or optionallysubstituted heteroaryl, wherein the heteroaryl substituents are alkyl,cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic,heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl,carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulphamoyl,sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or when positionedadjacent to each other, may combine to form cycloalkyl orheteroalicyclic ring systems; X₃ is CH₂, CH(R₇), C(R₇)(R₇), NH, N(R₃),O, or S; wherein each R₇ independently is amino, amino carbonyl,hydroxy, acyl, optionally substituted alkoxy, wherein the alkylsubstituents are cyano, halogen, hydroxyl, alkylamino, dialkylamino,amido, alkylamido, dialkylamido, alkanoyl, alkoxy, sulfonamido, nitro,aryl, or heteroaryl, optionally substituted aryloxy, wherein the arylsubstituents are cyano, halogen, hydroxyl, nitro, trifluoromethyl,alkyl, alkylthio, alkoxy, amino, alkylamino, dialkylamino, alkanoyl,amido, N-alkylamido, NN-dialkylamino, sulfonamido, aryl, or heteroaryl,optionally substituted alkyl, wherein the alkyl substituents are cyano,halogen, hydroxyl, alkylamino, dialkylamino, amido, alkylamido,dialkylamido, alkanoyl, alkoxy, sulfonamido, nitro, aryl, or heteroaryl,optionally substituted cycloalkyl, wherein the cycloalkyl substituentsare alkyl, cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl,heteroalicyclic, heteroaryl, acyl, amidino, amido, amino, alkyoxyamino,carbamoyl, carboxy, cyano, ether, hydroxyl, imino, halo, nitro,sulphamoyl, sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or oneor more ring carbons may be bonded via a double bond to a group selectedfrom NH, S and O, optionally substituted arylalkyl, wherein the arylsubstituents are cyano, halogen, hydroxyl, nitro, trifluoromethyl,alkyl, alkylthio, alkoxy, amino, alkylamino, dialkylamino, alkanoyl,amido, N-alkylamido, N,N-dialkylamino, sulfonamido, aryl, or heteroaryl,optionally substituted aryl, wherein the aryl substituents are cyano,halogen, hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy,amino, alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,NN-dialkylamino, sulfonamido, aryl, or heteroaryl, or optionallysubstituted heteroaryl, wherein the heteroaryl substituents are alkyl,cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic,heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl,carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulphamoyl,sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or when positionedadjacent to each other, may combine to form cycloalkyl orheteroalicyclic ring systems; R₈ is acyl, optionally substituted alkyl,wherein the alkyl substituents are cyano, halogen, hydroxyl, alkylamino,dialkylamino, amido, alkylamido, dialkylamido, alkanoyl, alkoxy,sulfonamido, nitro, aryl, or heteroaryl, optionally substitutedcycloalkyl, wherein the cycloalkyl substituents are alkyl, cycloalkyl,—O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic, heteroaryl,acyl, amidino, amido, amino, alkyoxyamino, carbamoyl, carboxy, cyano,ether, hydroxyl, imino, halo, nitro, sulphamoyl, sulfonyl, sulphinyl,sulphenyl, sulfonamido or urea, or one or more ring carbons may bebonded via a double bond to a group selected from NH, S and O,optionally substituted arylalkyl, wherein the aryl substituents arecyano, halogen, hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio,alkoxy, amino, alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, optionallysubstituted aryl, wherein aryl the substituents are cyano, halogen,hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, amino,alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, or optionallysubstituted heteroaryl, wherein the heteroaryl substituents are alkyl,cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic,heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl,carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulphamoyl,sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or when positionedadjacent to each other, may combine to form cycloalkyl orheteroalicyclic ring systems; R₂₄ and R₂₅ are the same or different andeach is hydrogen, optionally substituted alkyl, wherein the alkylsubstituents are cyano, halogen, hydroxyl, alkylamino, dialkylamino,amido, alkylamido, dialkylamido, alkanoyl, alkoxy, sulfonamido, nitro,aryl, or heteroaryl, optionally substituted cycloalkyl, wherein thecycloalkyl substituents are alkyl, cycloalkyl, —O—C(halogen)₃, biaryl,carbocyclic aryl, heteroalicyclic, heteroaryl, acyl, amidino, amido,amino, alkyoxyamino, carbamoyl, carboxy, cyano, ether, hydroxyl, imino,halo, nitro, sulphamoyl, sulfonyl, sulphinyl, sulphenyl, sulfonamido orurea, or one or more ring carbons may be bonded via a double bond to agroup selected from NH, S and O, optionally substituted arylalkyl,wherein the aryl substituents are cyano, halogen, hydroxyl, nitro,trifluoromethyl, alkyl, alkylthio, alkoxy, amino, alkylamino,dialkylamino, alkanoyl, amido, N-alkylamido, NN-dialkylamino,sulfonamido, aryl, or heteroaryl, optionally substituted aryl, whereinthe aryl substituents are cyano, halogen, hydroxyl, nitro,trifluoromethyl, alkyl, alkylthio, alkoxy, amino, alkylamino,dialkylamino, alkanoyl, amido, N-alkylamido, N,N-dialkylamino,sulfonamido, aryl, or heteroaryl, or optionally substituted heteroaryl,wherein the heteroaryl substituents are alkyl, cycloalkyl,—O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic, heteroaryl,acyl, amidino, amido, amino, alkyoxyamino, carbamoyl, carboxy, cyano,ether, hydroxyl, imino, halo, nitro, sulphamoyl, sulfonyl, sulphinyl,sulphenyl, sulfonamido or urea, or when positioned adjacent to eachother, may combine to form cycloalkyl or heteroalicyclic ring systems;n=1 or 2; and m=1, 2 or
 3. 6. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: X₁ is C(═O); R₁is selected from the group consisting of optionally substitutedarylalkyl, wherein the aryl substituents are cyano, halogen, hydroxyl,nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, amino, alkylamino,dialkylamino, alkanoyl, amido, N-alkylamido, N,N-dialkylamino,sulfonamido, aryl, or heteroaryl, and optionally substitutedheteroarylalkyl, wherein the heteroaryl substituents are alkyl,cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic,heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl,carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulphamoyl,sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or when positionedadjacent to each other, may combine to form cycloalkyl orheteroalicyclic ring systems; R₂ is formula (VI):

wherein R₁₁, R₁₂, R₁₃, R₁₄, and R₁₅ are the same or different and eachis hydrogen, halogen, hydroxy, amino, acyl, cyano, and optionallysubstituted C₁₋₃alkyl, wherein the substituents are cyano, halogen,hydroxyl, alkylamino, dialkylamino, amido, alkylamido, dialkylamido,alkanoyl, alkoxy, sulfonamido, nitro, aryl, or heteroaryl, or any of thepairs R₁₁ and R₁₂, or R₁₂ and R₁₃, or R₁₃ and R₁₄, or R₁₄ and R₁₅ may betaken together to form an optionally substituted saturated or partiallysaturated 5-7 membered heterocyclic or carbocyclic ring, wherein theheterocyclic or carbocyclic ring substituents are alkyl, cycloalkyl,—O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic, heteroaryl,acyl, amidino, amido, amino, alkyoxyamino, carbamoyl, carboxy, cyano,ether, hydroxyl, imino, halo, nitro, sulphamoyl, sulfonyl, sulphinyl,sulphenyl, sulfonamido or urea; R₃ is selected from the group consistingof hydrogen, halogen, hydroxy, alkoxy, aryloxy, optionally substitutedalkyl, wherein the alkyl substituents are cyano, halogen, hydroxyl,nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, amino, alkylamino,dialkylamino, alkanoyl, amido, N-alkylamido, N,N-dialkylamino,sulfonamido, aryl, or heteroaryl, amino, amino sulfonyl, and cyano; R₄and R₅ together with the N to which they are attached form a saturatedor partially saturated 4-7 membered ring with the general formula (II):

wherein: X₂ is C(═O), CH₂, CH(R₆), or C(R₆)(R₆); wherein each R₆independently is amino, amino carbonyl, hydroxy, acyl, optionallysubstituted alkoxy, wherein the alkyl substituents are cyano, halogen,hydroxyl, alkylamino, dialkylamino, amido, alkylamido, dialkylamido,alkanoyl, alkoxy, sulfonamido, nitro, aryl, or heteroaryl, optionallysubstituted aryloxy, wherein the aryl substituents are cyano, halogen,hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, amino,alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, optionallysubstituted alkyl, wherein the alkyl substituents are cyano, halogen,hydroxyl, alkylamino, dialkylamino, amido, alkylamido, dialkylamido,alkanoyl, alkoxy, sulfonamido, nitro, aryl, or heteroaryl, optionallysubstituted cycloalkyl, wherein the cycloalkyl substituents are alkyl,cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic,heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl,carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulphamoyl,sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or one or more ringcarbons may be bonded via a double bond to a group selected from NH, Sand O, optionally substituted arylalkyl, wherein the aryl substituentsare cyano, halogen, hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio,alkoxy, amino, alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, optionallysubstituted aryl, wherein the aryl substituents are cyano, halogen,hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, amino,alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, or optionallysubstituted heteroaryl, wherein the heteroaryl substituents are alkyl,cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic,heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl,carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulphamoyl,sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or when positionedadjacent to each other, may combine to form cycloalkyl orheteroalicyclic ring systems; X₃ is CH₂, CH(R₇), C(R₇)(R₇), NH, N(R₈),O, or S; wherein each R₇ independently is amino, amino carbonyl,hydroxy, acyl, optionally substituted alkoxy, wherein the alkylsubstituents are cyano, halogen, hydroxyl, alkylamino, dialkylamino,amido, alkylamido, dialkylamido, alkanoyl, alkoxy, sulfonamido, nitro,aryl, or heteroaryl, optionally substituted aryloxy, wherein the arylsubstituents are cyano, halogen, hydroxyl, nitro, trifluoromethyl,alkyl, alkylthio, alkoxy, amino, alkylamino, dialkylamino, alkanoyl,amido, N-alkylamido, N,N-dialkylamino, sulfonamido, aryl, or heteroaryl,optionally substituted alkyl, wherein the alkyl substituents are cyano,halogen, hydroxyl, alkylamino, dialkylamino, amido, alkylamido,dialkylamido, alkanoyl, alkoxy, sulfonamido, nitro, aryl, or heteroaryl,optionally substituted cycloalkyl, wherein the cycloalkyl substituentsare alkyl, cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl,heteroalicyclic, heteroaryl, acyl, amidino, amido, amino, alkyoxyamino,carbamoyl, carboxy, cyano, ether, hydroxyl, imino, halo, nitro,sulphamoyl, sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or oneor more ring carbons may be bonded via a double bond to a group selectedfrom NH, S and O, optionally substituted arylalkyl, wherein the arylsubstituents are cyano, halogen, hydroxyl, nitro, trifluoromethyl,alkyl, alkylthio, alkoxy, amino, alkylamino, dialkylamino, alkanoyl,amido, N-alkylamido, N,N-dialkylamino, sulfonamido, aryl, or heteroaryl,optionally substituted aryl, wherein the aryl substituents are cyano,halogen, hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy,amino, alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, or optionallysubstituted heteroaryl, wherein the heteroaryl substituents are alkyl,cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic,heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl,carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulphamoyl,sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or when positionedadjacent to each other, may combine to form cycloalkyl orheteroalicyclic ring systems; R₈ is acyl, optionally substituted alkyl,wherein the alkyl substituents are cyano, halogen, hydroxyl, alkylamino,dialkylamino, amido, alkylamido, dialkylamido, alkanoyl, alkoxy,sulfonamido, nitro, aryl, or heteroaryl, optionally substitutedcycloalkyl, wherein the cycloalkyl substituents are alkyl, cycloalkyl,—O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic, heteroaryl,acyl, amidino, amido, amino, alkyoxyamino, carbamoyl, carboxy, cyano,ether, hydroxyl, imino, halo, nitro, sulphamoyl, sulfonyl, sulphinyl,sulphenyl, sulfonamido or urea, or one or more ring carbons may bebonded via a double bond to a group selected from NH, S and O,optionally substituted arylalkyl, wherein the aryl substituents arecyano, halogen, hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio,alkoxy, amino, alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, optionallysubstituted aryl, wherein aryl the substituents are cyano, halogen,hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, amino,alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, or optionallysubstituted heteroaryl, wherein the heteroaryl substituents are alkyl,cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic,heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl,carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulphamoyl,sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or when positionedadjacent to each other, may combine to form cycloalkyl orheteroalicyclic ring systems; R₂₄ and R₂₅ are the same or different andeach is hydrogen, optionally substituted alkyl, wherein the alkylsubstituents are cyano, halogen, hydroxyl, alkylamino, dialkylamino,amido, alkylamido, dialkylamido, alkanoyl, alkoxy, sulfonamido, nitro,aryl, or heteroaryl, optionally substituted cycloalkyl, wherein thecycloalkyl substituents are alkyl, cycloalkyl, —O—C(halogen)₃, biaryl,carbocyclic aryl, heteroalicyclic, heteroaryl, acyl, amidino, amido,amino, alkyoxyamino, carbamoyl, carboxy, cyano, ether, hydroxyl, imino,halo, nitro, sulphamoyl, sulfonyl, sulphinyl, sulphenyl, sulfonamido orurea, or one or more ring carbons may be bonded via a double bond to agroup selected from NH, S and O, optionally substituted arylalkyl,wherein the aryl substituents are cyano, halogen, hydroxyl, nitro,trifluoromethyl, alkyl, alkylthio, alkoxy, amino, alkylamino,dialkylamino, alkanoyl, amido, N-alkylamido, N,N-dialkylamino,sulfonamido, aryl, or heteroaryl, optionally substituted aryl, whereinthe aryl substituents are cyano, halogen, hydroxyl, nitro,trifluoromethyl, alkyl, alkylthio, alkoxy, amino, alkylamino,dialkylamino, alkanoyl, amido, N-alkylamido, N,N-dialkylamino,sulfonamido, aryl, or heteroaryl, or optionally substituted heteroaryl,wherein the heteroaryl substituents are alkyl, cycloalkyl,—O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic, heteroaryl,acyl, amidino, amido, amino, alkyoxyamino, carbamoyl, carboxy, cyano,ether, hydroxyl, imino, halo, nitro, sulphamoyl, sulfonyl, sulphinyl,sulphenyl, sulfonamido or urea, or when positioned adjacent to eachother, may combine to form cycloalkyl or heteroalicyclic ring systems;n=1 or 2; and m=1, 2 or
 3. 7. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: X₁ is selectedfrom the group consisting of CH₂, C(═O), C(═NH), and NC(═O); R₁ isformula (VII):

wherein: R₁₆, R₁₇, R₁₈, R₁₉ and R₂₀ are the same or different and eachis hydrogen, halogen, hydroxy, amino, acyl, cyano, optionallysubstituted C₁₋₃ alkyl, wherein the C₁₋₃ alkyl substituents are cyano,halogen, hydroxyl, alkylamino, dialkylamino, amino, alkylamido,dialkylamido, alkanoyl, alkoxy, sulfonamido, nitro, aryl, or heteroaryl,or optionally substituted alkoxy, wherein the C₁₋₃ alkyl substituentsare cyano, halogen, hydroxyl, alkylamino, dialkylamino, amido,alkylamido, dialkylamido, alkanoyl, alkoxy, sulfonamido, nitro, aryl, orheteroaryl; R₂₁ and R₂₂ are the same or different and each representshydrogen, hydroxy, and optionally substituted C₁₋₃ alkyl, wherein theC₁₋₃ alkyl substituents are cyano, halogen, hydroxyl, alkylamino,dialkylamino, amido, alkylamido, dialkylamido, alkanoyl, alkoxy,sulfonamido, nitro, aryl, or heteroaryl; R₂ is selected from the groupconsisting of optionally substituted alkyl, wherein the alkylsubstituents are cyano, halogen, hydroxyl, alkylamino, dialkylamino,amido, alkylamido, dialkylamido, alkanoyl, alkoxy, sulfonamido, nitro,aryl, or heteroaryl, optionally substituted aryl, wherein the arylsubstituents are cyano, halogen, hydroxyl, nitro, trifluoromethyl,alkyl, alkylthio, alkoxy, amino, alkylamino, dialkylamino, alkanoyl,amido, N-alkylamido, N,N-dialkylamino, sulfonamido, aryl, or heteroaryl,optionally substituted heteroaryl, wherein the heteroaryl substituentsare alkyl, cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl,heteroalicyclic, heteroaryl, acyl, amidino, amido, amino, alkyoxyamino,carbamoyl, carboxy, cyano, ether, hydroxyl, imino, halo, nitro,sulphamoyl, sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or whenpositioned adjacent to each other, may combine to form cycloalkyl orheteroalicyclic ring systems, and NR₂₄R₂₅; R₃ is selected from the groupconsisting of hydrogen, halogen, hydroxy, alkoxy, aryloxy, optionallysubstituted alkyl, wherein the alkyl substituents are cyano, halogen,hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, amino,alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, amino, aminosulfonyl, and cyano; R₄ and R₅ together with the N to which they areattached form a saturated or partially saturated 4-7 membered ring withthe general formula (II):

wherein: X₂ is C(═O), CH₂, CH(R₆), or C(R₆)(R₆); wherein each R₆independently is amino, amino carbonyl, hydroxy, acyl, optionallysubstituted alkoxy, wherein the alkyl substituents are cyano, halogen,hydroxyl, alkylamino, dialkylamino, amido, alkylamido, dialkylamido,alkanoyl, alkoxy, sulfonamido, nitro, aryl, or heteroaryl, optionallysubstituted aryloxy, wherein the aryl substituents are cyano, halogen,hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, amino,alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, optionallysubstituted alkyl, wherein the alkyl substituents are cyano, halogen,hydroxyl, alkylamino, dialkylamino, amido, alkylamido, dialkylamido,alkanoyl, alkoxy, sulfonamido, nitro, aryl, or heteroaryl, optionallysubstituted cycloalkyl, wherein the cycloalkyl substituents are alkyl,cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic,heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl,carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulphamoyl,sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or one or more ringcarbons may be bonded via a double bond to a group selected from NH, Sand O, optionally substituted arylalkyl, wherein the aryl substituentsare cyano, halogen, hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio,alkoxy, amino, alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, optionallysubstituted aryl, wherein the aryl substituents are cyano, halogen,hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, amino,alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, or optionallysubstituted heteroaryl, wherein the heteroaryl substituents are alkyl,cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic,heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl,carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulphamoyl,sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or when positionedadjacent to each other, may combine to form cycloalkyl orheteroalicyclic ring systems; X₃ is CH₂, CH(R₇), C(R₇)(R₇), NH, N(R₈),O, or S; wherein each R₇ independently is amino, amino carbonyl,hydroxy, acyl, optionally substituted alkoxy, wherein the alkylsubstituents are cyano, halogen, hydroxyl, alkylamino, dialkylamino,amido, alkylamido, dialkylamido, alkanoyl, alkoxy, sulfonamido, nitro,aryl, or heteroaryl, optionally substituted aryloxy, wherein the arylsubstituents are cyano, halogen, hydroxyl, nitro, trifluoromethyl,alkyl, alkylthio, alkoxy, amino, alkylamino, dialkylamino, alkanoyl,amido, N-alkylamido, N,N-dialkylamino, sulfonamido, aryl, or heteroaryl,optionally substituted alkyl, wherein the alkyl substituents are cyano,halogen, hydroxyl, alkylamino, dialkylamino, amido, alkylamido,dialkylamido, alkanoyl, alkoxy, sulfonamido, nitro, aryl, or heteroaryl,optionally substituted cycloalkyl, wherein the cycloalkyl substituentsare alkyl, cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl,heteroalicyclic, heteroaryl, acyl, amidino, amido, amino, alkyoxyamino,carbamoyl, carboxy, cyano, ether, hydroxyl, imino, halo, nitro,sulphamoyl, sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or oneor more ring carbons may be bonded via a double bond to a group selectedfrom NH, S and O, optionally substituted arylalkyl, wherein the arylsubstituents are cyano, halogen, hydroxyl, nitro, trifluoromethyl,alkyl, alkylthio, alkoxy, amino, alkylamino, dialkylamino, alkanoyl,amido, N-alkylamido, N,N-dialkylamino, sulfonamido, aryl, or heteroaryl,optionally substituted aryl, wherein the aryl substituents are cyano,halogen, hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy,amino, alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,NN-dialkylamino, sulfonamido, aryl, or heteroaryl, or optionallysubstituted heteroaryl, wherein the heteroaryl substituents are alkyl,cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic,heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl,carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulphamoyl,sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or when positionedadjacent to each other, may combine to form cycloalkyl orheteroalicyclic ring systems; R₈ is acyl, optionally substituted alkyl,wherein the alkyl substituents are cyano, halogen, hydroxyl, alkylamino,dialkylamino, amido, alkylamido, dialkylamido, alkanoyl, alkoxy,sulfonamido, nitro, aryl, or heteroaryl, optionally substitutedcycloalkyl, wherein the cycloalkyl substituents are alkyl, cycloalkyl,—O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic, heteroaryl,acyl, amidino, amido, amino, alkyoxyamino, carbamoyl, carboxy, cyano,ether, hydroxyl, imino, halo, nitro, sulphamoyl, sulfonyl, sulphinyl,sulphenyl, sulfonamido or urea, or one or more ring carbons may bebonded via a double bond to a group selected from NH, S and O,optionally substituted arylalkyl, wherein the aryl substituents arecyano, halogen, hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio,alkoxy, amino, alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, optionallysubstituted aryl, wherein aryl the substituents are cyano, halogen,hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, amino,alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, or optionallysubstituted heteroaryl, wherein the heteroaryl substituents are alkyl,cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic,heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl,carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulphamoyl,sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or when positionedadjacent to each other, may combine to form cycloalkyl orheteroalicyclic ring systems; R₂₄ and R₂₅ are the same or different andeach is hydrogen, optionally substituted alkyl, wherein the alkylsubstituents are cyano, halogen, hydroxyl, alkylamino, dialkylamino,amido, alkylamido, dialkylamido, alkanoyl, alkoxy, sulfonamido, nitro,aryl, or heteroaryl, optionally substituted cycloalkyl, wherein thecycloalkyl substituents are alkyl, cycloalkyl, —O—C(halogen)₃, biaryl,carbocyclic aryl, heteroalicyclic, heteroaryl, acyl, amidino, amido,amino, alkyoxyamino, carbamoyl, carboxy, cyano, ether, hydroxyl, imino,halo, nitro, sulphamoyl, sulfonyl, sulphinyl, sulphenyl, sulfonamido orurea, or one or more ring carbons may be bonded via a double bond to agroup selected from NH, S and O, optionally substituted arylalkyl,wherein the aryl substituents are cyano, halogen, hydroxyl, nitro,trifluoromethyl, alkyl, alkylthio, alkoxy, amino, alkylamino,dialkylamino, alkanoyl, amido, N-alkylamido, N,N-dialkylamino,sulfonamido, aryl, or heteroaryl, optionally substituted aryl, whereinthe aryl substituents are cyano, halogen, hydroxyl, nitro,trifluoromethyl, alkyl, alkylthio, alkoxy, amino, alkylamino,dialkylamino, alkanoyl, amido, N-alkylamido, N,N-dialkylamino,sulfonamido, aryl, or heteroaryl, or optionally substituted heteroaryl,wherein the heteroaryl substituents are alkyl, cycloalkyl,—O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic, heteroaryl,acyl, amidino, amido, amino, alkyoxyamino, carbamoyl, carboxy, cyano,ether, hydroxyl, imino, halo, nitro, sulphamoyl, sulfonyl, sulphinyl,sulphenyl, sulfonamido or urea, or when positioned adjacent to eachother, may combine to form cycloalkyl or heteroalicyclic ring systems;n=1 or 2; and m=1, 2 or
 3. 8. A compound according to claim 1 wherein R₃is H, F, or CH₃, or a pharmaceutically acceptable salt thereof.
 9. Acompound according to claim 8, wherein R₃ is H or F, or apharmaceutically acceptable salt thereof.
 10. A compound according toclaim 1, wherein R₄ and R₅ together with the N to which they areattached form a saturated or partially saturated 4-6 membered ring withthe general formula (II), or a pharmaceutically acceptable salt thereof.11. A compound according to claim 10, wherein the 4-6 membered ring issubstituted azetidinyl, substituted pyrrolidinyl, substitutedpiperazinyl or substituted piperidinyl, or a pharmaceutically acceptablesalt thereof.
 12. A compound having Formula (VIII):

or a pharmaceutically acceptable salt thereof, wherein: R₂ is selectedfrom the group consisting of NR₂₄R₂₅, formula (III), formula (IV),formula (V), and formula (VI):

wherein: A, D, E, G, and J are the same or different and each is C or N,with the provisos that in each instance: 1) at least one of A, D, E, G,or J is N; 2) when R₂ is formula (III), E may also be O or S; and 3)when R₂ is formula (IV), A may also be O or S; R₉ and R₁₀ are the sameor different and each is hydrogen, halogen, hydroxy, cyano, amino, acyl,optionally substituted C₁₋₃ alkyl, wherein the C₁₋₃ alkyl substituentsare cyano, halogen, hydroxyl, alkylamino, dialkylamino, amido,alkylamido, dialkylamido, alkanoyl, alkoxy, sulfonamido, nitro, aryl, orheteroaryl, optionally substituted arylalkyl, wherein the arylsubstituents are cyano, halogen, hydroxyl, nitro, trifluoromethyl,alkyl, alkylthio, alkoxy, amino, alkylamino, dialkylamino, alkanoyl,amido, N-alkylamido, N,N-dialkylamino, sulfonamido, aryl, or heteroaryl,optionally substituted aryl, wherein the aryl substituents are cyano,halogen, hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy,amino, alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, or optionallysubstituted heteroaryl, wherein the heteroaryl substituents are alkyl,cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic,heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl,carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulphamoyl,sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea; or may be takentogether to form an optionally substituted saturated or partiallysaturated 5-7 membered heterocyclic or carbocyclic ring, wherein theheterocyclic or carbocyclic ring substituents are alkyl, cycloalkyl,—O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic, heteroaryl,acyl, amidino, amido, amino, alkyoxyamino, carbamoyl, carboxy, cyano,ether, hydroxyl, imino, halo, nitro, sulphamoyl, sulfonyl, sulphinyl,sulphenyl, sulfonamido or urea; R₁₁, R₁₂, R₁₃, R₁₄, and R₁₅ are the sameor different and each represents hydrogen, halogen, hydroxy, amino,acyl, cyano, and optionally substituted C₁₋₃alkyl, wherein the C₁₋₃alkyl substituents are cyano, halogen, hydroxyl, alkylamino,dialkylamino, amido, alkylamido, dialkylamido, alkanoyl, alkoxy,sulfonamido, nitro, aryl, or heteroaryl, or any of the pairs R₁₁ andR₁₂, or R₁₂ and R₁₃, or R₁₃ and R₁₄, or R₁₄ and R₁₅ may be takentogether to form an optionally substituted saturated or partiallysaturated 5-7 membered heterocyclic or carbocyclic ring, wherein theheterocyclic or carbocyclic ring substituents are alkyl, cycloalkyl,—O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic, heteroaryl,acyl, amidino, amido, amino, alkyoxyamino, carbamoyl, carboxy, cyano,ether, hydroxyl, imino, halo, nitro, sulphamoyl, sulfonyl, sulphinyl,sulphenyl, sulfonamido or urea; and R₁₆, R₁₇, R₁₈, R₁₉ and R₂₀ are thesame or different and each represents hydrogen, halogen, hydroxy, amino,acyl, cyano, optionally substituted C₁₋₃ alkyl, wherein the C₁₋₃ alkylsubstituents are cyano, halogen, hydroxyl, alkylamino, dialkylamino,amido, alkylamido, dialkylamido, alkanoyl, alkoxy, sulfonamido, nitro,aryl, or heteroaryl, or optionally substituted alkoxy, wherein the C₁₋₃alkyl substituents are cyano, halogen, hydroxyl, alkylamino,dialkylamino, amido, alkylamido, dialkylamido, alkanoyl, alkoxy,sulfonamido, nitro, aryl, or heteroaryl; R₃ is selected from the groupconsisting of hydrogen, halogen, hydroxy, alkoxy, aryloxy, optionallysubstituted alkyl, wherein the alkyl substituents are cyano, halogen,hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, amino,alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, amino, aminosulfonyl, and cyano; R₄ and R₅ together with the N to which they areattached form a saturated or partially saturated 4-7 membered ring withthe general formula (II):

wherein: X₂ is C(═O), CH₂, CH(R₆), or C(R₆)(R₆); wherein each R₆independently is amino, amino carbonyl, hydroxy, acyl, optionallysubstituted alkoxy, wherein the alkyl substituents are cyano, halogen,hydroxyl, alkylamino, dialkylamino, amido, alkylamido, dialkylamido,alkanoyl, alkoxy, sulfonamido, nitro, aryl, or heteroaryl, optionallysubstituted aryloxy, wherein the aryl substituents are cyano, halogen,hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, amino,alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, optionallysubstituted alkyl, wherein the alkyl substituents are cyano, halogen,hydroxyl, alkylamino, dialkylamino, amido, alkylamido, dialkylamido,alkanoyl, alkoxy, sulfonamido, nitro, aryl, or heteroaryl, optionallysubstituted cycloalkyl, wherein the cycloalkyl substituents are alkyl,cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic,heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl,carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulphamoyl,sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or one or more ringcarbons may be bonded via a double bond to a group selected from NH, Sand O, optionally substituted arylalkyl, wherein the aryl substituentsare cyano, halogen, hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio,alkoxy, amino, alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, optionallysubstituted aryl, wherein the aryl substituents are cyano, halogen,hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, amino,alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, or optionallysubstituted heteroaryl, wherein the heteroaryl substituents are alkyl,cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic,heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl,carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulphamoyl,sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or when positionedadjacent to each other, may combine to form cycloalkyl orheteroalicyclic ring systems; X₃ is CH₂, CH(R₇), C(R₇)(R₇), NH, N(R₈),O, or S; wherein each R₇ independently is amino, amino carbonyl,hydroxy, acyl, optionally substituted alkoxy, wherein the alkylsubstituents are cyano, halogen, hydroxyl, alkylamino, dialkylamino,amido, alkylamido, dialkylamido, alkanoyl, alkoxy, sulfonamido, nitro,aryl, or heteroaryl, optionally substituted aryloxy, wherein the arylsubstituents are cyano, halogen, hydroxyl, nitro, trifluoromethyl,alkyl, alkylthio, alkoxy, amino, alkylamino, dialkylamino, alkanoyl,amido, N-alkylamido, N,N-dialkylamino, sulfonamido, aryl, or heteroaryl,optionally substituted alkyl, wherein the alkyl substituents are cyano,halogen, hydroxyl, alkylamino, dialkylamino, amido, alkylamido,dialkylamido, alkanoyl, alkoxy, sulfonamido, nitro, aryl, or heteroaryl,optionally substituted cycloalkyl, wherein the cycloalkyl substituentsare alkyl, cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl,heteroalicyclic, heteroaryl, acyl, amidino, amido, amino, alkyoxyamino,carbamoyl, carboxy, cyano, ether, hydroxyl, imino, halo, nitro,sulphamoyl, sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or oneor more ring carbons may be bonded via a double bond to a group selectedfrom NH, S and O, optionally substituted arylalkyl, wherein the arylsubstituents are cyano, halogen, hydroxyl, nitro, trifluoromethyl,alkyl, alkylthio, alkoxy, amino, alkylamino, dialkylamino, alkanoyl,amido, N-alkylamido, N,N-dialkylamino, sulfonamido, aryl, or heteroaryl,optionally substituted aryl, wherein the aryl substituents are cyano,halogen, hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy,amino, alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, or optionallysubstituted heteroaryl, wherein the heteroaryl substituents are alkyl,cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic,heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl,carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulphamoyl,sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or when positionedadjacent to each other, may combine to form cycloalkyl orheteroalicyclic ring systems; R₈ is acyl, optionally substituted alkyl,wherein the alkyl substituents are cyano, halogen, hydroxyl, alkylamino,dialkylamino, amido, alkylamido, dialkylamido, alkanoyl, alkoxy,sulfonamido, nitro, aryl, or heteroaryl, optionally substitutedcycloalkyl, wherein the cycloalkyl substituents are alkyl, cycloalkyl,—O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic, heteroaryl,acyl, amidino, amido, amino, alkyoxyamino, carbamoyl, carboxy, cyano,ether, hydroxyl, imino, halo, nitro, sulphamoyl, sulfonyl, sulphinyl,sulphenyl, sulfonamido or urea, or one or more ring carbons may bebonded via a double bond to a group selected from NH, S and O,optionally substituted arylalkyl, wherein the aryl substituents arecyano, halogen, hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio,alkoxy, amino, alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, optionallysubstituted aryl, wherein aryl the substituents are cyano, halogen,hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, amino,alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,N,N-dialkylamino, sulfonamido, aryl, or heteroaryl, or optionallysubstituted heteroaryl, wherein the heteroaryl substituents are alkyl,cycloalkyl, —O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic,heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl,carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulphamoyl,sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea, or when positionedadjacent to each other, may combine to form cycloalkyl orheteroalicyclic ring systems; R₂₄ and R₂₅ are the same or different andeach is hydrogen, optionally substituted alkyl, wherein the alkylsubstituents are cyano, halogen, hydroxyl, alkylamino, dialkylamino,amido, alkylamido, dialkylamido, alkanoyl, alkoxy, sulfonamido, nitro,aryl, or heteroaryl, optionally substituted cycloalkyl, wherein thecycloalkyl substituents are alkyl, cycloalkyl, —O—C(halogen)₃, biaryl,carbocyclic aryl, heteroalicyclic, heteroaryl, acyl, amidino, amido,amino, alkyoxyamino, carbamoyl, carboxy, cyano, ether, hydroxyl, imino,halo, nitro, sulphamoyl, sulfonyl, sulphinyl, sulphenyl, sulfonamido orurea, or one or more ring carbons may be bonded via a double bond to agroup selected from NH, S and O, optionally substituted arylalkyl,wherein the aryl substituents are cyano, halogen, hydroxyl, nitro,trifluoromethyl, alkyl, alkylthio, alkoxy, amino, alkylamino,dialkylamino, alkanoyl, amido, N-alkylamido, N,N-dialkylamino,sulfonamido, aryl, or heteroaryl, optionally substituted aryl, whereinthe aryl substituents are cyano, halogen, hydroxyl, nitro,trifluoromethyl, alkyl, alkylthio, alkoxy, amino, alkylamino,dialkylamino, alkanoyl, amido, N-alkylamido, N,N-dialkylamino,sulfonamido, aryl, or heteroaryl, or optionally substituted heteroaryl,wherein the heteroaryl substituents are alkyl, cycloalkyl,—O—C(halogen)₃, biaryl, carbocyclic aryl, heteroalicyclic, heteroaryl,acyl, amidino, amido, amino, alkyoxyamino, carbamoyl, carboxy, cyano,ether, hydroxyl, imino, halo, nitro, sulphamoyl, sulfonyl, sulphinyl,sulphenyl, sulfonamido or urea, or when positioned adjacent to eachother, may combine to form cycloalkyl or heteroalicyclic ring systems;n=1 or 2; and m=1, 2 or
 3. 13. A compound according to claim 12 with theFormula (IX):

or a pharmaceutically acceptable salt thereof.
 14. A compound selectedfrom the group consisting of:N-Benzyl-N-[3-(4-phenyl-piperidine-1-carbonyl)-phenyl]-benzenesulfonamide;N-Benzyl-N-[3-(3-phenyl-piperidine-1-carbonyl)-phenyl]-benzenesulfonamide;N-Benzyl-N-[3-(2-phenyl-morpholine-4-carbonyl)-phenyl]-benzenesulfonamide;N-Benzyl-N-[3-(4-phenoxy-piperidine-1-carbonyl)-phenyl]-benzenesulfonamide;N-Benzyl-N-[3-(3-phenyl-piperidine-1-carbonyl)-phenyl]-methanesulfonamide;N-Benzyl-N-[3-(2-phenyl-morpholine-4-carbonyl)-phenyl]-methanesulfonamide;N-Benzyl-N-[3-(4-phenoxy-piperidine-1-carbonyl)-phenyl]-methanesulfonamide;N-Benzyl-N-[3-(4-phenyl-piperidine-1-carbonyl)-phenyl]-methanesulfonamide;1-Methyl-1H-imidazole-4-sulfonic acidbenzyl-[3-(4-phenyl-piperidine-1-carbonyl)-phenyl]-amide;N-Benzyl-N-[3-(morpholine-4-carbonyl)-phenyl]-benzenesulfonamide;1-Methyl-1H-imidazole-4-sulfonic acidbenzyl-[3-(2-phenyl-morpholine-4-carbonyl)-phenyl]-amide;N-Benzyl-2-fluoro-N-[3-(morpholine-4-carbonyl)-phenyl]-benzenesulfonamide;N-Benzyl-4-fluoro-N-[3-(morpholine-4-carbonyl)-phenyl]-benzenesulfonamide;1-Methyl-1H-imidazole-4-sulfonic acidbenzyl-{3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-phenyl}-amide;1-Methyl-1H-imidazole-4-sulfonic acidbenzyl-[3-(4-cyclohexylmethyl-piperazine-1-carbonyl)-phenyl]-amide;2,3-Dihydro-benzo[1,4]dioxine-6-sulfonic acidbenzyl-[3-(morpholine-4-carbonyl)-phenyl]-amide;4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonic acidbenzyl-[3-(morpholine-4-carbonyl)-phenyl]-amide;Benzo[1,2,5]oxadiazole-4-sulfonic acidbenzyl-[3-(morpholine-4-carbonyl)-phenyl]-amide;Benzo[1,3]dioxole-5-sulfonic acidbenzyl-[3-(morpholine-4-carbonyl)-phenyl]-amide;5-[Benzyl-(4-cyano-benzenesulfonyl)-amino]-2-fluoro-N-isopropyl-benzamide;5-[Benzyl-(3-cyano-benzenesulfonyl)-amino]-2-fluoro-N-isopropyl-benzamide;5-[Benzyl-(2-cyano-benzenesulfonyl)-amino]-2-fluoro-N-isopropyl-benzamide;5-[(4-Chloro-benzyl)-(3-cyano-benzenesulfonyl)-amino]-2-fluoro-N-(2-hydroxy-ethyl)-benzamide;5-[(4-Chloro-benzyl)-(3-cyano-benzenesulfonyl)-amino]-2-fluoro-N-(1-hydroxymethyl-propyl)-benzamide;N-(4-Chloro-benzyl)-3-cyano-N-[4-fluoro-3-(3-hydroxy-azetidine-1-carbonyl)-phenyl]-benzenesulfonamide;5-[(4-Chloro-benzyl)-(3-cyano-benzenesulfonyl)-amino]-2-fluoro-N-(2-hydroxy-1-hydroxymethyl-ethyl)-benzamide;5-[(4-Chloro-benzyl)-(3-cyano-benzenesulfonyl)-amino]-2-fluoro-N-(2-hydroxy-1-methyl-ethyl)-benzamide;5-[(4-Chloro-benzyl)-(3-cyano-benzenesulfonyl)-amino]-2-fluoro-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzamide;5-[(4-Chloro-benzyl)-(3-cyano-benzenesulfonyl)-amino]-2-fluoro-N-(2-methoxy-ethyl)-benzamide;N-(4-Chloro-benzyl)-3-cyano-N-[4-fluoro-3-(3-hydroxy-piperidine-1-carbonyl)-phenyl]-benzenesulfonamide;N-(4-Chloro-benzyl)-3-cyano-N-[4-fluoro-3-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-phenyl]-benzenesulfonamide;Pyridine-3-sulfonic acid(4-chloro-benzyl)-[3-(3-hydroxy-azetidine-1-carbonyl)-phenyl]-amide;Pyridine-3-sulfonic acid(4-chloro-benzyl)-[3-(3-hydroxy-piperidine-1-carbonyl)-phenyl]-amide;Pyridine-3-sulfonic acid(4-chloro-benzyl)-[3-((R)-3-fluoro-pyrrolidine-1-carbonyl)-phenyl]-amide;Pyridine-3-sulfonic acid[3-(azetidine-1-carbonyl)-phenyl]-(4-chloro-benzyl)-amide;1-Methyl-1H-imidazole-4-sulfonic acid[3-(azetidine-1-carbonyl)-phenyl]-(4-chloro-benzyl)-amide;1-Methyl-1H-pyrazole-3-sulfonic acid[3-(azetidine-1-carbonyl)-phenyl]-(4-chloro-benzyl)-amide; and1-Methyl-1H-pyrazole-3-sulfonic acid(4-chloro-benzyl)-[3-(3-methyl-piperidine-1-carbonyl)-phenyl]-amide; ora pharmaceutically acceptable salt thereof.
 15. A pharmaceuticalcomposition comprising at least one compound as claimed in claim 1, or apharmaceutically acceptable salt thereof, optionally together with oneor more pharmaceutically acceptable excipients, diluents and/orcarriers.
 16. A compound as claimed in claim 1, wherein R₂ is CH₃, or apharmaceutically acceptable salt thereof.
 17. A method for the treatmentof arrhythmia, psoriasis, rheumatoid arthritis, multiple sclerosis,type-1 diabetes, type-2 diabetes mellitus, or inflammatory boweldisorder, comprising administering to a subject an effective amount ofthe compound of claim 1, or a pharmaceutically acceptable salt thereof.18. The method as claimed in claim 17, wherein the disorder ispsoriasis, rheumatoid arthritis, multiple sclerosis or arrhythmia.